{"gene":"APLP2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1993,"finding":"APLP2 was isolated as a close homologue of APP, sharing domain architecture including a cytoplasmic domain predicted to couple with the GTP-binding protein G(o), suggesting APLP2 may function as a cell surface activator of this G protein.","method":"Molecular cloning, sequence analysis, expression analysis","journal":"Nature genetics","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction of G(o) coupling based on sequence; no direct biochemical validation","pmids":["8220435"],"is_preprint":false},{"year":1993,"finding":"APLP2 (also called APPH) encodes a type I transmembrane protein with a signal peptide, large extracellular domain including a Kunitz protease inhibitor domain, transmembrane region, and short cytoplasmic domain, establishing it as the closest known relative of APP in an emerging multigene family.","method":"Molecular cloning, cDNA sequencing, domain analysis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — molecular cloning with full sequence characterization; single study","pmids":["8485127"],"is_preprint":false},{"year":1994,"finding":"APLP2 is modified by chondroitin sulfate glycosaminoglycan (CS GAG) addition at a single site (Ser-614); a serine-to-alanine substitution at position 614 abolishes CS GAG modification, establishing this as the sole modification site.","method":"Stable transfection in CHO and COS-1 cells, chondroitinase AC digestion, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with functional readout, replicated in two cell lines","pmids":["8071334"],"is_preprint":false},{"year":1995,"finding":"CS GAG modification of APLP2 is regulated by alternative splicing: the APLP2-763 isoform containing a 12-amino acid insertion immediately N-terminal to Ser-614 is not modified by CS GAG, whereas the APLP2-751 isoform is. Similarly, APP isoforms lacking exon 15 (L-APP) are CS GAG modified while exon 15-containing isoforms are not.","method":"Transfection of isoform constructs, biochemical analysis of GAG modification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — isoform-specific mutagenesis/expression with clear biochemical readout","pmids":["7622456"],"is_preprint":false},{"year":1995,"finding":"APLP2 is enriched in postsynaptic compartments in cortex and hippocampus, but is abundant in presynaptic olfactory sensory axons and axon terminals in olfactory glomeruli; CS GAG-modified APLP2 mRNA is specifically enriched in the olfactory epithelium and CS-modified APLP2 accumulates in the olfactory bulb, consistent with a role in axonal pathfinding and/or synaptogenesis.","method":"Immunocytochemistry with APLP2-specific antibodies, confocal microscopy, biochemical fractionation, in situ hybridization","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by immunocytochemistry and confocal microscopy with biochemical validation","pmids":["7472397"],"is_preprint":false},{"year":1997,"finding":"APLP2 and APP are functionally redundant in vivo: APLP2 single knockout mice are viable and fertile, but APP/APLP2 double knockout mice show ~80% postnatal lethality within the first week, demonstrating that APLP2 and APP can substitute for each other functionally during early postnatal development.","method":"Gene targeting/knockout, genetic epistasis in double KO mice","journal":"Neurobiology of aging","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with clear postnatal lethality phenotype; seminal double KO study","pmids":["9461064"],"is_preprint":false},{"year":1998,"finding":"APLP2 is required for correct genomic segregation in dividing cells: homozygous APLP2 deletion arrests embryos before the blastocyst stage, and antisense suppression of APLP2 in embryonic fibroblasts produces daughter cells with abnormal DNA contents (>4C and <2C), indicating a role in mitotic genome segregation.","method":"Germline deletion, antisense RNA expression with GFP co-transfection, DNA content analysis by flow cytometry","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific cell division phenotype; single lab","pmids":["9707424"],"is_preprint":false},{"year":1999,"finding":"APP and APLP2 modulate copper homeostasis in vivo: APP(-/-) and APLP2(-/-) knockout mice show significantly elevated copper levels specifically in cerebral cortex (40% and 16% respectively) and liver (80% and 36% respectively), while zinc and iron levels are unaffected, indicating that APP and APLP2 expression specifically modulates copper homeostasis.","method":"Atomic absorption spectrophotometry in APP and APLP2 knockout mouse tissues","journal":"Brain research","confidence":"High","confidence_rationale":"Tier 2 — direct measurement in KO mice with tissue-specific and metal-specific readout; replicated across two KO lines","pmids":["10526140"],"is_preprint":false},{"year":1999,"finding":"The recombinant APLP2 ectodomain (sAPLP2) promotes neurite outgrowth in chick sympathetic neurons with activity similar to sAPP695 and sAPP751, supporting a neurotrophic function for APLP2 analogous to APP.","method":"Recombinant protein expression in Pichia pastoris, neurite outgrowth assay on chick sympathetic neurons","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay with recombinant protein; single lab","pmids":["9923612"],"is_preprint":false},{"year":2001,"finding":"APLP2 ectodomain shedding in corneal epithelial cells is regulated by PKC-epsilon and MAP kinase (MAPK) signaling: PKC activation by PMA and EGF increased APLP2 shedding, which was blocked by the MEK inhibitor U-0126, establishing that basal and stimulated APLP2 shedding requires MAPK activity.","method":"Western blotting, flow cytometry, pharmacological inhibitors (staurosporine, PKC-epsilon peptide inhibitor, U-0126) in corneal epithelial cells","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with multiple inhibitors; single lab","pmids":["11443060"],"is_preprint":false},{"year":2002,"finding":"APLP2 (like APP and APLP1) is cleaved by BACE1 and the resulting intracellular domain (ALID2) enhances Fe65-dependent gene activation in a transcriptional transactivation assay, indicating that BACE1/γ-secretase processing of APLP2 generates a transcriptionally active intracellular fragment.","method":"Overexpression of BACE1 with APLP2 in cells, co-transfection transcriptional reporter assays, biochemical analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical cleavage assay combined with transcriptional functional assay; replicated for APP family","pmids":["14699153","12228233"],"is_preprint":false},{"year":2002,"finding":"APLP2 intracellular domain (ALID2), produced by γ-secretase cleavage in a Presenilin 1-dependent manner, enhances Fe65-dependent gene activation, establishing that γ-secretase processing of APLP2 regulates transcription.","method":"Presenilin 1-dependent γ-secretase cleavage assays, transcriptional reporter assays with Fe65 co-transfection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical cleavage assay with functional transcriptional readout; Presenilin dependence demonstrated","pmids":["12228233"],"is_preprint":false},{"year":2004,"finding":"APLP2 is processed by α-secretase-like, β-secretase-like (BACE), γ-secretase-like, and ε-site cleavages in neuroblastoma cells; p3-like and Aβ-like fragments of APLP2 are detectable in cell media, and APLP2 processing is the most elaborate among APP family members with alternative cleavage sites.","method":"Stably transfected SH-SY5Y cells with C-terminally tagged constructs, pharmacological protease inhibitors, Western blotting, mass spectrometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic pharmacological dissection with tagged constructs and secreted fragment detection; multiple methods","pmids":["14970212"],"is_preprint":false},{"year":2004,"finding":"BACE1 modulates APLP2 processing in vivo: APLP2 proteolytic products are decreased in BACE knockout mice and increased in BACE transgenic mice; overexpression of BACE in cultured cells increases APLP2 processing.","method":"BACE knockout and transgenic mice, immunoblotting of brain extracts, BACE overexpression in cultured cells","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic manipulation (KO and transgenic) with biochemical readout; replicated in vivo and in vitro","pmids":["15080893"],"is_preprint":false},{"year":2004,"finding":"F-spondin binds the conserved central extracellular domain of APP and inhibits beta-secretase cleavage; APLP2 shares this domain and is subject to similar extracellular ligand-mediated regulation of processing.","method":"Binding assays, proteolytic cleavage assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 — F-spondin binding shown for APP; APLP2 involvement inferred from domain conservation only","pmids":["14983046"],"is_preprint":false},{"year":2005,"finding":"APLP2 shedding is mediated by the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17): overexpression of either enzyme in HEK293 cells increases soluble APLP2 release; ADAM10-preferring inhibitors most strongly block APLP2 shedding in neuroblastoma cells; ADAM10-transgenic mice show increased soluble APLP2 and C-terminal fragments.","method":"Overexpression of ADAM10/TACE in HEK293 cells, pharmacological inhibitors, ADAM10-transgenic mice, Western blotting","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function overexpression, inhibitor studies, and transgenic mice with biochemical readout; multiple orthogonal approaches","pmids":["16279945"],"is_preprint":false},{"year":2005,"finding":"APP and APLP2 homo- and heterodimerize and promote trans-cellular adhesion: all three APP family members form homo- and heterocomplexes; endogenous APLP2 is required for cell-cell adhesion in mouse embryonic fibroblasts; APP/APLP2 interact in synaptically enriched membrane compartments in mouse brain.","method":"Co-immunoprecipitation from mouse brain, cell aggregation assays with MEFs from APLP2 KO mice, subcellular fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP from brain, KO MEF adhesion assay with rescue; multiple orthogonal methods","pmids":["16193067"],"is_preprint":false},{"year":2005,"finding":"APP and APLP2 modulate Cu/Zn-nitric oxide-catalyzed degradation of glypican-1 heparan sulfate: in cell-free experiments, the Cu(I) form of APLP2 (and Cu(II) form) inhibits glypican-1 autodegradation; in primary cortical neurons and fibroblasts from APLP2 knockout mice, nitric oxide-catalyzed heparan sulfate degradation is increased, indicating APLP2 normally inhibits this process particularly in fibroblasts.","method":"Cell-free biochemical assays, confocal immunofluorescence, flow cytometry, primary neurons and fibroblasts from APP/APLP2 KO mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — cell-free reconstitution combined with KO cell functional assay and imaging; multiple methods","pmids":["15677459"],"is_preprint":false},{"year":2006,"finding":"PAT1a binds directly to the basolateral sorting signal of APLP2 (and APP/APLP1) cytoplasmic domains, co-localizes in trans-Golgi network vesicles/endosomes in primary neurons, and regulates APP/APLP2 cell surface levels and processing: PAT1a overexpression or knockdown modulates surface levels and promotes APP/APLP2 processing with increased Aβ secretion.","method":"Co-immunoprecipitation, co-localization in primary neurons, RNAi knockdown, overexpression, cell surface biotinylation, Aβ ELISA","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct binding shown by Co-IP, bidirectional manipulation (OE and KD) with biochemical readout; multiple orthogonal methods","pmids":["17050537"],"is_preprint":false},{"year":2006,"finding":"APLP2 KPI domain functions as a Kunitz serine proteinase inhibitor that inhibits plasma clotting in vitro; APLP2(-/-) mice show shorter times to carotid artery occlusion (prothrombotic phenotype) and smaller intracerebral hematomas, demonstrating that APLP2 exerts anticoagulant function via its KPI domain in vivo.","method":"Recombinant KPI domain expression, plasma clotting assays, carotid artery thrombosis model, intracerebral hemorrhage model in APLP2(-/-) mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzymatic inhibition assay plus KO mouse in vivo thrombosis model with functional readout","pmids":["19403832"],"is_preprint":false},{"year":2006,"finding":"Keratinocytes from APP/APLP2 double-knockout mice show reduced proliferation (~40% reduction in vivo and in vitro), reduced migration velocity, and compromised cell-substrate adhesion; these defects can be rescued by exogenous recombinant sAPPα, indicating that APP/APLP2-derived soluble ectodomains are required for keratinocyte proliferation, adhesion, and migration.","method":"Primary keratinocytes from APP/APLP2 KO mice, proliferation assays, migration assays, adhesion assays, rescue with recombinant sAPPα","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — KO primary cells with rescue experiment; multiple cellular phenotype readouts","pmids":["16584729"],"is_preprint":false},{"year":2008,"finding":"APP and APLP2 are essential modulators of glucose and insulin homeostasis: APP/APLP2 double knockout mice show 66% lower plasma glucose and hyperinsulinemia at birth; single knockouts also show hyperinsulinemia and ~31% lower plasma glucose, and reduced plasma calcium, magnesium, phosphate, and growth restriction.","method":"APP/APLP2 double and single KO mice, plasma glucose, insulin, calcium, magnesium, phosphate measurements at embryonic day E17 and postnatally","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with quantitative metabolic phenotyping; double and single KO comparison","pmids":["18393365"],"is_preprint":false},{"year":2008,"finding":"Loss of APP and APLP2 in embryonic stem cell-derived glutamatergic neurons leads to decreased VGLUT2 expression (mRNA and protein) and reduced glutamate uptake/release; blocking γ-secretase cleavage of APP in WT neurons similarly reduces VGLUT2; and VGLUT2 levels can be restored by a construct encoding the APP C-terminal intracellular domain, establishing that APP/APLP2 intracellular domain signaling regulates glutamatergic neurotransmission.","method":"ESC differentiation to neurons from APP/APLP2 double KO, γ-secretase inhibition, APP intracellular domain rescue construct, VGLUT2 mRNA/protein quantification, glutamate uptake assay, hippocampal organotypic slice electrophysiology","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 1–2 — KO neurons, pharmacological inhibition, domain rescue, electrophysiology; multiple orthogonal methods","pmids":["18535156"],"is_preprint":false},{"year":2009,"finding":"APP, APLP1, and APLP2 form homo- and heterotypic cis interactions via two conserved regions; APLP2 and APP primarily localize to intracellular compartments (unlike APLP1 which is mostly at the cell surface); APLP1 uniquely forms trans interactions; and co-expression of APP with APLP1 or APLP2 diminishes Aβ42 generation due to heteromeric complex formation.","method":"Live cell imaging, FRET, co-immunoprecipitation, deletion mutants in multiple cell lines","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — FRET and Co-IP with deletion mutants; localization by live imaging; functional Aβ readout","pmids":["19126676"],"is_preprint":false},{"year":2011,"finding":"APLP2 and APP are synergistically required for neuromuscular transmission: APPsα-DM (APP secreted ectodomain knock-in on APLP2-null background) mice show reduced quantal content, depleted readily releasable pool, fragmented postsynaptic specializations, and muscular weakness; these deficits are associated with loss of an APP/Mint2/Munc18 complex; additionally, APPsα-DM mice show impaired hippocampal LTP and spatial learning.","method":"Genetic double mutant (APPsα-KI × APLP2-KO), electrophysiological recordings at NMJ, co-immunoprecipitation of APP/Mint2/Munc18 complex, behavioral assays, GABA-A rescue experiment","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with electrophysiological readout, Co-IP of complex, behavioral phenotyping; multiple orthogonal methods","pmids":["21522131"],"is_preprint":false},{"year":2011,"finding":"APLP2 mediates signaling via Mint3-Taz and Mint3-Yap transcriptional complexes: APLP2 forms transcriptionally active triple complexes with Mint3 and each of the co-activators Taz and Yap; complex formation and nuclear translocation are regulated by γ-secretase cleavage of APLP2; presence of Mint1 instead of Mint3 prevents nuclear translocation.","method":"Co-immunoprecipitation, transcriptional reporter assays, γ-secretase inhibitor treatment, subcellular fractionation","journal":"Journal of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and reporter assays; single lab, moderate evidence","pmids":["21178287"],"is_preprint":false},{"year":2012,"finding":"Bat3 interacts with APLP2, enhances its stability by reducing ubiquitination and proteasomal degradation; the proline-rich domain of Bat3 is required for this binding; nuclear export of Bat3 under apoptotic stimulation elevates APLP2 levels, promoting cell survival.","method":"Co-immunoprecipitation, domain deletion constructs, ubiquitination assays, proteasome inhibitor treatment, apoptosis assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping, ubiquitination assay, functional apoptosis readout; single lab","pmids":["22641691"],"is_preprint":false},{"year":2013,"finding":"APLP2 is required for cell cycle exit of cortical progenitors during neurogenesis: APLP2 silencing in vivo in an APP/APLP1 double knockout background causes cortical progenitors to remain undifferentiated with higher mitotic cell numbers, establishing a specific role for APLP2 in priming cortical progenitors for neuronal differentiation.","method":"In vivo shRNA silencing in APP/APLP1 double KO mouse background, BrdU/EdU labeling, immunostaining, mitotic index quantification","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic epistasis (triple loss-of-function) with quantitative cell proliferation readout","pmids":["23345401"],"is_preprint":false},{"year":2013,"finding":"PCSK9 interacts directly and in a pH-dependent manner with APLP2 (but not APP) via its C-terminal domain; APLP2 (but not APP) mediates postendocytic delivery of PCSK9 to lysosomes and is required for PCSK9 function in targeting LDLR for degradation.","method":"Co-immunoprecipitation, pH-dependent binding assays, APLP2 knockdown/KO functional assays measuring LDLR levels and lysosomal delivery","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay with pH characterization, functional KO/knockdown with LDLR readout; mechanistically defined","pmids":["23430252"],"is_preprint":false},{"year":2014,"finding":"APP/APLP2 expression is required to initiate endosome-to-nucleus transport of glypican-1-derived anhydromannose-containing heparan sulfate (HS): nuclear translocation of HS is absent in APP(-/-) and APLP2(-/-) MEFs, restored by APP transfection, and blocked by β- or γ-secretase inhibitors in WT cells, suggesting that APP/APLP2 degradation products mediate HS nuclear import.","method":"Deconvolution immunofluorescence microscopy with anMan-specific antibody, 35S labeling, secretase inhibitors, APP KO rescue transfection, confocal microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — KO plus rescue transfection, pharmacological inhibition, and imaging; multiple orthogonal methods","pmids":["24898256"],"is_preprint":false},{"year":2015,"finding":"APP and APLP2 interact with the synaptic release machinery (presynaptic proteins) via the NH2-terminal region of their intracellular domain; a naturally produced peptide JCasp (from γ-secretase/caspase double cleavage of APP) interferes with this interaction and reduces glutamate release in hippocampal slices from WT but not APP-deficient mice; deletion of APP and APLP2 produces synaptic deficits consistent with facilitated transmitter release.","method":"Domain mapping, cell-penetrating peptide (JCasp), glutamate release assays in acute hippocampal slices, APP/APLP2 double KO electrophysiology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — domain mapping with functional peptide interference and KO electrophysiology; multiple orthogonal methods","pmids":["26551565"],"is_preprint":false},{"year":2015,"finding":"APLP2 regulates refractive eye development: Aplp2 knockout mice develop high hyperopia (+11.5 D) and exhibit dose-dependent reduction in susceptibility to environmentally induced myopia; this phenotype is associated with reduced contrast sensitivity and changes in electrophysiological properties of retinal amacrine cells, which express Aplp2.","method":"Aplp2 KO mice, refraction measurement, visual evoked potentials, electroretinography, retinal cell type immunostaining","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with quantitative refractive phenotype, dose-response (het vs homo), and cellular mechanism identification","pmids":["26313004"],"is_preprint":false},{"year":2015,"finding":"APLP1 and APLP2 associate with assembled NMDA receptors (GluN1/GluN2A and GluN1/GluN2B) via interaction with the obligatory GluN1 subunit in both transfected cells and adult mammalian brain extracts; like APP, APLP2 enhances GluN1/GluN2A and GluN1/GluN2B surface expression.","method":"Co-immunoprecipitation from transfected mammalian cells and adult brain detergent extracts, cell surface expression assays","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP from brain and cells; single lab, functional surface expression readout","pmids":["25683482"],"is_preprint":false},{"year":2015,"finding":"APLP2 affects the actin cytoskeleton in pancreatic cancer cells: APLP2 knockdown decreases cortical actin and increases intracellular actin filaments; stable APLP2 knockdown reduces pancreatic cancer cell migration, invasion, and orthotopic tumor metastasis in vivo.","method":"Inducible shRNA knockdown, phalloidin staining/actin imaging, migration/invasion assays, orthotopic tumor mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with actin cytoskeleton readout and in vivo tumor model; single lab","pmids":["25576918"],"is_preprint":false},{"year":2016,"finding":"Zinc induces multimerization of APLP2 (and APP/APLP1) and enriches them at cellular adhesion sites; however, unlike APLP1, zinc does not facilitate de novo APLP2-containing adhesion complex formation; zinc binding prevents cleavage of APLP2 by extracellular secretases.","method":"Live-cell microscopy, microcontact printing adhesion assay, ELISA for shed ectodomains, zinc treatment in cell culture and rat neurons","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct imaging and functional adhesion assay with zinc treatment; single lab","pmids":["26801522"],"is_preprint":false},{"year":2017,"finding":"APP, APLP2, and LRP1 all interact with PCSK9; however, infusion of PCSK9 into App(-/-), Aplp2(-/-), Aplp2-depleted App(-/-), or liver-specific Lrp1(-/-) mice reduces hepatic LDLR levels similarly to WT, demonstrating that APP, APLP2, and LRP1 are not required for PCSK9-mediated LDLR degradation in vivo.","method":"Co-immunoprecipitation, PCSK9 infusion into multiple KO mouse lines, hepatic LDLR quantification","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic KO mouse models with quantitative in vivo functional readout; contradicts prior claim about APLP2 being required for PCSK9 function","pmids":["28495363"],"is_preprint":false},{"year":2020,"finding":"APP and APLP2 are required in GABAergic forebrain neurons for synaptic plasticity and cognition: conditional double KO in GABAergic neurons (DlxCre) causes cognitive deficits, impaired LTP, altered basal synaptic transmission at Schaffer collateral/CA1, reduced action potential firing of CA1 pyramidal cells, and disrupted excitation/inhibition balance.","method":"Conditional double KO (DlxCre), hippocampal slice electrophysiology, behavioral tests (spatial learning, nesting, burrowing), neuronal morphology analysis","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with electrophysiology, behavior, and morphology readouts; multiple orthogonal methods","pmids":["32219307"],"is_preprint":false},{"year":2021,"finding":"APP and APLP2 control neuronal Ca2+ homeostasis: loss of both APP and APLP2 (but not APLP2 alone) impairs Ca2+ handling, endoplasmic reticulum Ca2+ store refill, and synaptic plasticity via altered SERCA-ATPase function and expression of store-operated Ca2+ channel proteins Stim1 and Stim2; long-term AAV-mediated APPsα expression restores Ca2+ homeostasis and LTP in APP/APLP2 cDKO cultures.","method":"Conditional double KO hippocampal neurons, Ca2+ imaging, ER Ca2+ store measurements, SERCA ATPase functional assays, Stim1/2 protein expression, AAV-APPsα rescue, LTP electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — KO with molecular mechanism (SERCA/Stim1/2), functional rescue by APPsα expression, multiple orthogonal methods","pmids":["34172567"],"is_preprint":false},{"year":2022,"finding":"APLP2 in spinal GABAergic inhibitory interneurons interacts trans-cellularly with microglia-specific integrin CD11b; peripheral nerve injury reduces spinal APLP2 specifically in GABAergic interneurons, and targeted APLP2 knockdown in GAD2-positive neurons disrupts this APLP2-CD11b interaction, causing microglia-dependent pain sensitization.","method":"Conditional knockdown in GAD2-Cre mice, co-immunoprecipitation of APLP2/CD11b, immunostaining, behavioral pain assays, microglial activation markers","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific KD with Co-IP interaction and behavioral readout; single lab","pmids":["36442651"],"is_preprint":false},{"year":2023,"finding":"The APLP2 intracellular domain (AICD2), generated by γ-secretase cleavage, translocates to the nucleus and interacts with NF-κB p65, enhancing NF-κB transcriptional activity to upregulate IL-1β and iNOS expression; this pathway is exploited for antimycobacterial defense, and M. tuberculosis suppresses APLP2 expression to evade this host response.","method":"APLP2 knockdown/mutant macrophages, APLP2 mutant mice, nuclear AICD2 co-immunoprecipitation with p65, NF-κB reporter assay, iNOS/IL-1β expression, M. bovis BCG infection model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of AICD2/p65 in nucleus, reporter assay, KO mouse infection model; single lab","pmids":["37844466"],"is_preprint":false},{"year":2023,"finding":"YWK-II/APLP2 inhibits TGF-β signaling by interacting with TGFBR2 in a TGF-β-dependent manner and binding Hsp90, thereby interfering with the TGFBR2-Hsp90 stabilization interaction, leading to enhanced ubiquitination and degradation of TGFBR2.","method":"Co-immunoprecipitation (APLP2/TGFBR2 and APLP2/Hsp90), ubiquitination assays, TGFBR2 stability assays upon APLP2 knockdown/overexpression, TGF-β signaling reporter assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with multiple partners, ubiquitination assay, functional signaling readout; single lab","pmids":["37479189"],"is_preprint":false},{"year":2023,"finding":"In human cerebrospinal fluid, APLP2 ectodomain shedding occurs predominantly via β-secretase-like activity (not α-secretase as in HEK293 cells); APLP2 undergoes intramembranous cleavage at three sites by γ-secretase, establishing the in vivo processing pattern of APLP2 in the human CNS.","method":"Novel anti-APLP2 juxtamembrane antibody (OA603), HEK293 overexpression, human CSF analysis, MALDI mass spectrometry for cleavage site identification","journal":"Psychogeriatrics","confidence":"Medium","confidence_rationale":"Tier 1 — mass spectrometry cleavage site identification in human CSF; single lab but rigorous method","pmids":["36691315"],"is_preprint":false},{"year":2018,"finding":"APLP2 expression promotes JNK-dependent cell migration in Drosophila: ectopic APLP2 expression induces cell migration that is suppressed by JNK loss-of-function and enhanced by JNK gain-of-function; APLP2 activates JNK signaling by promoting JNK phosphorylation, which triggers MMP1 expression required for basement membrane degradation.","method":"Drosophila ectopic expression, JNK pathway genetic epistasis (loss- and gain-of-function), JNK phosphorylation assay, MMP1 expression analysis","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila with molecular readout (JNK phosphorylation, MMP1); ortholog study","pmids":["30155482"],"is_preprint":false},{"year":2025,"finding":"APLP2 binds K-Ras indirectly via C-Raf, as identified by TurboID-based proximity proteomics and validated by BRET and co-immunoprecipitation assays.","method":"TurboID proximity proteomics, BRET assay, co-immunoprecipitation","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 — proximity proteomics and Co-IP; preprint, single lab, indirect interaction only","pmids":["bio_10.1101_2025.06.13.659437"],"is_preprint":true},{"year":1996,"finding":"FE65L (hFE65L), a human homologue of rat FE65, interacts with the cytoplasmic domain of APLP2 (but not APLP1) via a single phosphotyrosine interaction (PI) domain binding the NPXY motif; endogenous APP and APLP2 co-immunoprecipitate with HA-tagged hFE65L from mammalian cells.","method":"Yeast two-hybrid screening, co-immunoprecipitation from mammalian cells overexpressing HA-hFE65L","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by Co-IP from mammalian cells; single lab","pmids":["8855266"],"is_preprint":false},{"year":1999,"finding":"Disabled-1 (Dab1) interacts with APLP2 (and APP and APLP1) via its PI domain binding the conserved cytoplasmic NPxY motif; co-transfection of APP family members increases serine phosphorylation of Dab1.","method":"Yeast two-hybrid, biochemical co-immunoprecipitation, co-transfection phosphorylation assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by biochemical Co-IP; functional phosphorylation readout; single lab","pmids":["10460257"],"is_preprint":false},{"year":2013,"finding":"APLP2 co-immunoprecipitates with and downregulates MHC class I surface expression on Ewing's sarcoma cells; irradiation induces redistribution of APLP2 to cell surface, correlated with reduced MHC class I surface expression; siRNA knockdown of APLP2 increases MHC class I surface expression.","method":"Co-immunoprecipitation of APLP2/MHC class I, siRNA knockdown, flow cytometry surface staining, irradiation treatment","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP interaction with functional surface expression readout by flow cytometry and siRNA; single lab","pmids":["24353913"],"is_preprint":false}],"current_model":"APLP2 is a type I transmembrane glycoprotein of the APP family that undergoes regulated ectodomain shedding by ADAM10/TACE and sequential cleavage by β-secretase (BACE1) and γ-secretase/ε-site to release a transcriptionally active intracellular domain (ALID2/AICD2) that forms complexes with Fe65, Mint3, and co-activators Taz/Yap to regulate gene expression including NF-κB targets; APLP2 homo- and heterodimerizes with APP/APLP1 to mediate trans-cellular adhesion and modulate Aβ generation; it interacts with presynaptic release machinery (via its intracellular domain), NMDA receptors (via GluN1), Mint2/Munc18, and the adaptor PAT1a to regulate intracellular trafficking; it controls copper homeostasis, Ca²⁺ homeostasis (via SERCA/Stim1/Stim2), and glypican-1 heparan sulfate processing; its KPI domain inhibits coagulation proteases to exert anticoagulant function; it undergoes chondroitin sulfate GAG modification at Ser-614 in an isoform-specific manner; and genetic studies in mice demonstrate functional redundancy with APP for postnatal survival, neuromuscular transmission, synaptic plasticity, cortical neurogenesis, glucose homeostasis, and refractive eye development."},"narrative":{"teleology":[{"year":1993,"claim":"Molecular cloning established APLP2 as the closest APP homologue, defining its shared domain architecture (signal peptide, KPI domain, transmembrane segment, cytoplasmic NPXY motif) and raising the question of whether the two proteins have overlapping functions.","evidence":"cDNA cloning and sequence/domain analysis from two independent groups","pmids":["8220435","8485127"],"confidence":"Medium","gaps":["No functional data; domain homology does not prove functional equivalence","Predicted G(o)-coupling lacked biochemical validation"]},{"year":1994,"claim":"Identification of Ser-614 as the sole chondroitin sulfate GAG modification site, and the subsequent demonstration that alternative splicing controls GAG addition, revealed an isoform-specific post-translational modification with potential implications for axonal targeting.","evidence":"Site-directed mutagenesis in CHO/COS-1 cells with chondroitinase digestion; isoform-specific expression analysis","pmids":["8071334","7622456"],"confidence":"High","gaps":["Functional consequence of CS-GAG modification on APLP2 biology remained undefined","Mechanism by which the 12-aa insertion blocks GAG addition was not determined structurally"]},{"year":1997,"claim":"The demonstration that APP/APLP2 double knockout mice die postnatally while single knockouts are viable established functional redundancy between the two genes and motivated all subsequent compound genetic analyses.","evidence":"Gene targeting and double-KO mouse generation with postnatal lethality phenotype","pmids":["9461064"],"confidence":"High","gaps":["Molecular basis of postnatal lethality was undefined","Whether APLP1 could also compensate remained to be tested"]},{"year":1999,"claim":"Loss-of-function studies in knockout mice revealed APLP2's role in copper homeostasis and its neurotrophic properties, broadening the functional repertoire beyond structural homology with APP.","evidence":"Atomic absorption spectrophotometry in APLP2-KO mouse tissues; recombinant sAPLP2 neurite outgrowth assay in chick sympathetic neurons","pmids":["10526140","9923612"],"confidence":"High","gaps":["Copper-binding site on APLP2 not mapped","Receptor mediating sAPLP2 neurotrophic activity unknown"]},{"year":2002,"claim":"Discovery that BACE1 and γ-secretase sequentially cleave APLP2 to release a transcriptionally active intracellular domain (ALID2) that activates Fe65-dependent gene expression established APLP2 as a signaling molecule processed analogously to Notch.","evidence":"BACE1 overexpression cleavage assays combined with transcriptional reporter assays; Presenilin 1-dependent γ-secretase cleavage demonstration","pmids":["12228233","14699153"],"confidence":"High","gaps":["Endogenous target genes of ALID2/Fe65 were not identified","Physiological relevance of ALID2 signaling in vivo not established"]},{"year":2005,"claim":"Identification of ADAM10 and TACE as the α-secretases mediating APLP2 ectodomain shedding, combined with the discovery that APP/APLP2 homo- and heterodimerize to mediate trans-cellular adhesion, integrated APLP2 into both regulated proteolysis and cell adhesion pathways.","evidence":"ADAM10/TACE overexpression and inhibitor studies in cells plus ADAM10-transgenic mice; Co-IP from mouse brain and KO MEF adhesion assays with rescue","pmids":["16279945","16193067"],"confidence":"High","gaps":["Structural basis of homo/heterodimerization interface not resolved","Relative contributions of cis vs. trans dimerization to adhesion in vivo unclear"]},{"year":2006,"claim":"The KPI domain of APLP2 was shown to inhibit coagulation proteases with anticoagulant effects in vivo, and the trafficking adaptor PAT1a was identified as a regulator of APLP2 surface levels and processing, establishing two distinct functional axes—hemostasis and intracellular trafficking.","evidence":"Recombinant KPI domain clotting assays and APLP2-KO thrombosis models; PAT1a Co-IP, RNAi, and surface biotinylation in primary neurons","pmids":["19403832","17050537"],"confidence":"High","gaps":["In vivo bleeding/clotting phenotype in humans not assessed","PAT1a binding stoichiometry and competition with Fe65 not determined"]},{"year":2008,"claim":"APP/APLP2 double knockouts revealed essential roles in glucose/insulin homeostasis and glutamatergic neurotransmission (via VGLUT2 regulation by the intracellular domain), connecting APLP2 to metabolic and synaptic functions.","evidence":"Double-KO metabolic phenotyping; ESC-derived neurons from double-KO with γ-secretase inhibition and APP-ICD rescue, VGLUT2 quantification, electrophysiology","pmids":["18393365","18535156"],"confidence":"High","gaps":["Whether APLP2 alone is sufficient for glucose homeostasis not separated from APP contribution","Mechanism linking intracellular domain to VGLUT2 transcription not fully defined"]},{"year":2011,"claim":"Electrophysiological studies in compound mutant mice established that APP and APLP2 are synergistically required for neuromuscular transmission and hippocampal LTP, with the underlying mechanism involving an APP/Mint2/Munc18 presynaptic complex and Mint3-Taz/Yap transcriptional complexes.","evidence":"APPsα-KI × APLP2-KO mice with NMJ and hippocampal electrophysiology, Co-IP of APP/Mint2/Munc18; Co-IP and reporter assays for Mint3-Taz/Yap complexes","pmids":["21522131","21178287"],"confidence":"High","gaps":["Direct target genes of Mint3-Taz/Yap complexes downstream of APLP2 not identified","Whether APLP2 directly recruits Mint2/Munc18 or acts indirectly through APP not resolved"]},{"year":2013,"claim":"APLP2 was shown to have unique functions not shared with APP: it mediates PCSK9-dependent LDLR lysosomal degradation and is specifically required for cortical progenitor cell cycle exit during neurogenesis, although the PCSK9 requirement was later challenged.","evidence":"APLP2 KD/KO with LDLR readout and pH-dependent binding assays; in vivo shRNA in APP/APLP1-DKO background with mitotic index quantification; PCSK9 infusion in multiple KO lines contradicting APLP2 requirement","pmids":["23430252","23345401","28495363"],"confidence":"High","gaps":["PCSK9/APLP2 interaction is contested—in vivo infusion studies found APLP2 dispensable for PCSK9 function","Neurogenesis mechanism downstream of APLP2 (transcriptional targets, signaling pathway) not identified"]},{"year":2015,"claim":"Multiple studies converged on synaptic and sensory functions: APLP2's intracellular domain interacts with presynaptic release machinery to regulate glutamate release; APLP2 associates with NMDA receptors via GluN1 to enhance their surface expression; and Aplp2 knockout mice develop hyperopia with altered retinal amacrine cell function.","evidence":"Domain mapping and JCasp peptide interference with hippocampal slice electrophysiology; Co-IP of APLP2/GluN1 from brain; Aplp2-KO refraction, ERG, and retinal immunostaining","pmids":["26551565","25683482","26313004"],"confidence":"High","gaps":["Structural basis of APLP2-GluN1 interaction not resolved","Molecular pathway linking APLP2 to amacrine cell physiology and emmetropization unknown"]},{"year":2021,"claim":"The mechanism by which APP/APLP2 control synaptic plasticity was traced to Ca²⁺ homeostasis: double knockout disrupts ER Ca²⁺ store refilling via altered SERCA function and Stim1/Stim2 expression, and this is rescued by secreted APPsα, linking ectodomain shedding to ER calcium signaling.","evidence":"Conditional double-KO hippocampal neurons with Ca²⁺ imaging, SERCA assays, Stim1/2 quantification, AAV-APPsα rescue, and LTP electrophysiology","pmids":["34172567"],"confidence":"High","gaps":["Whether APLP2-derived soluble ectodomain alone can rescue Ca²⁺ defects not tested","Identity of the receptor mediating APPsα's effect on SERCA/Stim expression unknown"]},{"year":2023,"claim":"The transcriptional output of the APLP2 intracellular domain was extended to NF-κB signaling: nuclear AICD2 interacts with NF-κB p65 to upregulate IL-1β and iNOS in macrophages, and this antimicrobial pathway is exploited during mycobacterial defense; simultaneously, APLP2 was shown to inhibit TGF-β signaling by disrupting TGFBR2-Hsp90 stabilization.","evidence":"Co-IP of nuclear AICD2/p65, NF-κB reporter, KO mouse infection model; Co-IP of APLP2/TGFBR2/Hsp90 with ubiquitination and signaling readouts","pmids":["37844466","37479189"],"confidence":"Medium","gaps":["NF-κB target gene repertoire regulated by AICD2 not comprehensively defined","TGF-β pathway modulation studied only in overexpression systems","Neither finding independently replicated"]},{"year":null,"claim":"Key unresolved questions include the structural basis of APLP2 dimerization interfaces, the full transcriptional target repertoire of ALID2/AICD2 in vivo, whether the contested PCSK9-APLP2 axis is physiologically relevant, and the receptor(s) mediating sAPLP2 neurotrophic and Ca²⁺-regulatory signaling.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of full-length APLP2 or its dimerization interface","ChIP-seq or equivalent genome-wide identification of AICD2 targets not performed","Receptor for soluble APLP2 ectodomain signaling remains unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[16,20,34]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10,11,25,39]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[19,40]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[18,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,16,23,46]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[25,39]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[18,23]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[8,15,41]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[22,24,30,32,36,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,25,39,40,42]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[19]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[16,20,38]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3,10,11,12,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[27,31]}],"complexes":["APP family homo/heterodimer complex","ALID2/Fe65 transcriptional complex","Mint3-Taz/Yap transcriptional complex","APP/Mint2/Munc18 presynaptic complex"],"partners":["APP","APLP1","FE65","MINT3","ADAM10","BACE1","PCSK9","GLUN1"],"other_free_text":[]},"mechanistic_narrative":"APLP2 is a type I transmembrane glycoprotein of the APP family that functions as a multifunctional regulator of cell adhesion, synaptic transmission, intracellular signaling, and metabolic homeostasis. APLP2 undergoes regulated ectodomain shedding by ADAM10/TACE and sequential intramembranous cleavage by β-secretase (BACE1) and γ-secretase to release a transcriptionally active intracellular domain (ALID2/AICD2) that activates gene expression through complexes with Fe65, Mint3, and co-activators Taz/Yap, as well as through NF-κB p65 [PMID:12228233, PMID:21178287, PMID:37844466]. APLP2 homo- and heterodimerizes with APP and APLP1 to mediate trans-cellular adhesion, and its intracellular domain interacts with presynaptic release machinery, NMDA receptor subunit GluN1, Mint2/Munc18, and the trafficking adaptor PAT1a to regulate neurotransmitter release, synaptic plasticity, and Ca²⁺ homeostasis via SERCA and Stim1/Stim2 [PMID:16193067, PMID:21522131, PMID:25683482, PMID:34172567]. Genetic studies in mice reveal essential, functionally redundant roles with APP in postnatal survival, neuromuscular junction integrity, cortical neurogenesis, glucose/insulin homeostasis, copper homeostasis, refractive eye development, and anticoagulation via its Kunitz protease inhibitor domain [PMID:9461064, PMID:23345401, PMID:18393365, PMID:10526140, PMID:26313004, PMID:19403832]."},"prefetch_data":{"uniprot":{"accession":"Q06481","full_name":"Amyloid beta precursor like protein 2","aliases":["APPH","Amyloid beta (A4) precursor-like protein 2","Amyloid protein homolog","Amyloid-like protein 2","APLP-2","CDEI box-binding protein","CDEBP","Sperm membrane protein YWK-II"],"length_aa":763,"mass_kda":87.0,"function":"May play a role in the regulation of hemostasis. The soluble form may have inhibitory properties towards coagulation factors. May interact with cellular G-protein signaling pathways. May bind to the DNA 5'-GTCACATG-3'(CDEI box). Inhibits trypsin, chymotrypsin, plasmin, factor XIA and plasma and glandular kallikrein. Modulates the Cu/Zn nitric oxide-catalyzed autodegradation of GPC1 heparan sulfate side chains in fibroblasts (By similarity)","subcellular_location":"Cell membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q06481/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/APLP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"APPL2","ensg_id":"ENSG00000136044","cell_line_id":"CID000672","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"AHSA1","stoichiometry":0.2},{"gene":"PSME3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000672","total_profiled":1310},"omim":[{"mim_id":"617515","title":"RHOMBOID DOMAIN-CONTAINING 1; RHBDD1","url":"https://www.omim.org/entry/617515"},{"mim_id":"608124","title":"XYLOSYLTRANSFERASE 1; XYLT1","url":"https://www.omim.org/entry/608124"},{"mim_id":"602710","title":"AMYLOID BETA A4 PRECURSOR PROTEIN-BINDING, FAMILY B, MEMBER 2; APBB2","url":"https://www.omim.org/entry/602710"},{"mim_id":"120520","title":"MEMBRANE METALLOENDOPEPTIDASE; MME","url":"https://www.omim.org/entry/120520"},{"mim_id":"107770","title":"LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 1; LRP1","url":"https://www.omim.org/entry/107770"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/APLP2"},"hgnc":{"alias_symbol":["APPH"],"prev_symbol":["APPL2"]},"alphafold":{"accession":"Q06481","domains":[{"cath_id":"3.90.570.10","chopping":"52-136","consensus_level":"high","plddt":87.6595,"start":52,"end":136},{"cath_id":"3.30.1490.140","chopping":"151-205","consensus_level":"high","plddt":92.8027,"start":151,"end":205},{"cath_id":"4.10.410.10","chopping":"300-364","consensus_level":"high","plddt":88.0675,"start":300,"end":364},{"cath_id":"1.20.120.770","chopping":"374-456","consensus_level":"high","plddt":90.1201,"start":374,"end":456},{"cath_id":"1.20.120.770","chopping":"482-577","consensus_level":"high","plddt":88.3395,"start":482,"end":577}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06481","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q06481-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q06481-F1-predicted_aligned_error_v6.png","plddt_mean":68.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=APLP2","jax_strain_url":"https://www.jax.org/strain/search?query=APLP2"},"sequence":{"accession":"Q06481","fasta_url":"https://rest.uniprot.org/uniprotkb/Q06481.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q06481/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q06481"}},"corpus_meta":[{"pmid":"8220435","id":"PMC_8220435","title":"Isolation 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single site (Ser-614); a serine-to-alanine substitution at position 614 abolishes CS GAG modification.\",\n      \"method\": \"Stable transfection of CHO and COS-1 cells, chondroitinase AC digestion, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assay with mutagenesis identifying the precise modification site\",\n      \"pmids\": [\"8071334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CS GAG modification of APLP2 isoforms is regulated by alternative splicing: the APLP2-763 isoform, which contains a 12-amino-acid insertion immediately N-terminal to Ser-614, is not modified by CS GAG, whereas APLP2-751 is modified. Similarly, APP isoforms lacking exon 15 sequences (L-APP) are also CS GAG-modified.\",\n      \"method\": \"Cell transfection, GAG modification analysis, alternative splicing characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization with splice variant controls, replicated across APP and APLP2\",\n      \"pmids\": [\"7622456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"APLP2 is enriched in postsynaptic compartments in cortex and hippocampus, but is abundant in olfactory sensory axons and axon terminals in glomeruli (both pre- and postsynaptic compartments), with CS GAG-modified forms enriched in olfactory epithelium relative to CS GAG-free forms.\",\n      \"method\": \"Immunocytochemistry, confocal microscopy, biochemical fractionation with APLP2-specific antibodies\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by confocal microscopy and fractionation with specific antibodies\",\n      \"pmids\": [\"7472397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"APLP2 and APP are functionally redundant in vivo: APLP2 single knockout mice are viable and fertile, but APP/APLP2 double knockout mice show ~80% early postnatal lethality, indicating that APP and APLP2 are required for early postnatal development and can substitute for each other.\",\n      \"method\": \"Gene targeting/knockout, double knockout mouse generation, phenotypic analysis\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via double KO with defined lethal phenotype, replicated across multiple labs\",\n      \"pmids\": [\"9461064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"APLP2 is required for correct genomic segregation in dividing mouse cells: homozygous deletion of APLP2 arrests embryos before the blastocyst stage with abnormal DNA content (>4C and <2C), and antisense knockdown in embryonic fibroblasts produces daughter cells with abnormal DNA contents, indicating a role in mitotic genome segregation.\",\n      \"method\": \"Gene targeting (large deletion), DNA content analysis, antisense RNA expression in primary fibroblasts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific DNA segregation phenotype, two experimental systems\",\n      \"pmids\": [\"9707424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"APP and APLP2 expression specifically modulates copper homeostasis: APP(-/-) and APLP2(-/-) mice show significantly elevated copper levels in cerebral cortex and liver compared to wild-type, with no changes in zinc or iron levels.\",\n      \"method\": \"Atomic absorption spectrophotometry of knockout mouse tissues\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with specific elemental readout, but mechanistic link is indirect\",\n      \"pmids\": [\"10526140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Recombinant soluble APLP2 ectodomain (sAPLP2) promotes neurite outgrowth in chick sympathetic neurons with activity similar to sAPP695 and sAPP751.\",\n      \"method\": \"Recombinant protein expression in Pichia pastoris, neurite outgrowth assay on primary chick neurons\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reconstituted in vitro biological activity with purified recombinant protein\",\n      \"pmids\": [\"9923612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"APLP2 ectodomain shedding in corneal epithelial cells is regulated by PKC-epsilon and MAP kinase (MEK/ERK) signaling: PKC activation (PMA) and EGF stimulate APLP2 shedding, both of which are blocked by the MEK inhibitor U-0126; basal shedding also requires MAPK activity.\",\n      \"method\": \"Western blotting, flow cytometry, pharmacological inhibitors (staurosporine, PKC-epsilon peptide inhibitor, U-0126)\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection of signaling pathway with multiple inhibitors\",\n      \"pmids\": [\"11443060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"APLP2 is processed by alpha-, beta-, gamma-, and epsilon-secretase-like cleavages, generating C-terminal fragments and intracellular domains; APLP2 processing is the most elaborate among APP family members and involves alternative cleavage sites; Abeta-like and p3-like fragments of APLP2 are detectable in conditioned media.\",\n      \"method\": \"C-terminally tagged constructs in stably transfected SH-SY5Y cells, pharmacological protease inhibitors, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical characterization with specific inhibitors and detection of defined cleavage products\",\n      \"pmids\": [\"14970212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BACE (beta-secretase) modulates APLP2 processing in vivo: BACE knockout mice show decreased APLP2 proteolytic products, BACE transgenic mice show increased products, and BACE overexpression in cultured cells increases APLP2 processing.\",\n      \"method\": \"BACE KO and transgenic mice, cultured cells, Western blotting\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated in KO, transgenic, and cell culture systems; consistent directional results\",\n      \"pmids\": [\"15080893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APLP2 is a substrate for the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17), which shed its ectodomain: overexpression of either proteinase increases soluble APLP2 release, neuron-specific ADAM10 overexpression in transgenic mice increases soluble APLP2 and its C-terminal fragments, and an ADAM10-preferring inhibitor causes the strongest inhibition of APLP2 shedding in neuroblastoma cells.\",\n      \"method\": \"HEK293 overexpression, ADAM10 transgenic mice, pharmacological inhibitors, Western blotting\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (overexpression, transgenic mice, inhibitors) all consistent\",\n      \"pmids\": [\"16279945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APP (but not APLP2) stimulates glypican-1 heparan sulfate autodegradation in the presence of Cu(II) and Zn(II); APLP2 (both Cu forms) and the Cu(I) form of APP inhibit autodegradation. In primary cortical neurons from APP or APLP2 knockout mice, nitric oxide-catalyzed HS degradation is increased compared to wild-type, indicating that both APP and APLP2 modulate glypican-1 HS processing.\",\n      \"method\": \"Cell-free biochemical assays, confocal immunofluorescence, flow cytometry, knockout mouse neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods but functional distinctions between APP and APLP2 make mechanistic interpretation complex\",\n      \"pmids\": [\"15677459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PAT1a binds directly to APP, APLP1, and APLP2 intracellular domains (specifically the basolateral sorting signal) in vivo, co-localizes with them in trans-Golgi network vesicles or endosomes in primary neurons, and modulates their transport to the cell surface and processing: PAT1a overexpression or knockdown alters APP/APLP surface levels and promotes processing including increased Abeta secretion.\",\n      \"method\": \"Co-immunoprecipitation, co-localization in primary neurons, surface biotinylation, siRNA knockdown, overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed, localization in neurons, functional consequence (surface levels and processing) with gain- and loss-of-function\",\n      \"pmids\": [\"17050537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"APP and APLP2 double-knockout keratinocytes show reduced proliferation (~40% in vivo), impaired migration, severely compromised cell-substrate adhesion in vitro, and die within the first week of culture; the proliferation defect can be rescued by exogenous recombinant sAPPalpha, demonstrating a functional role for APP family ectodomain shedding in keratinocyte biology.\",\n      \"method\": \"Knockout mouse keratinocyte culture, proliferation assays, migration assays, adhesion assays, rescue with recombinant sAPPalpha\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined phenotype in DKO cells with rescue experiment, but mechanism is indirect\",\n      \"pmids\": [\"16584729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APP and APLP2 double knockout mice show postnatal hypoglycemia (66% lower plasma glucose), hyperinsulinemia, and reduced plasma calcium, magnesium, and phosphate, identifying a shared function of APP and APLP2 in modulating plasma insulin and glucose homeostasis.\",\n      \"method\": \"Plasma biochemistry in double knockout mice at gestational day E17 and postnatal day 0-1\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with specific metabolic phenotype; mechanism not resolved beyond loss-of-function\",\n      \"pmids\": [\"18393365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of APP and APLP2 in embryonic stem cell-derived glutamatergic neurons leads to decreased VGLUT2 expression (mRNA and protein) and reduced glutamate uptake/release; gamma-secretase blockade mimics this effect, and restoration of the APP C-terminal intracellular domain rescues VGLUT2 levels, indicating that APP/APLP2 regulate glutamatergic neurotransmission through their intracellular domain signaling.\",\n      \"method\": \"ESC-derived neurons from DKO mice, VGLUT2 mRNA/protein quantification, glutamate uptake assay, gamma-secretase inhibition, intracellular domain rescue construct, hippocampal organotypic slice electrophysiology\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including pharmacological inhibition, rescue with domain construct, and electrophysiology\",\n      \"pmids\": [\"18535156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"APLP1 mainly localizes to the cell surface whereas APP and APLP2 are mostly found in intracellular compartments (live cell imaging). APP family members form homo- and heterotypic cis interactions via FRET and co-immunoprecipitation; the N-terminal half of the ectodomain is crucial for APP and APLP2 interactions. Coexpression of APP with APLP1 or APLP2 leads to diminished Abeta42 generation, attributed to heteromeric complex formation.\",\n      \"method\": \"Live cell imaging, FRET, co-immunoprecipitation, deletion mutant analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging for localization, FRET + co-IP for interactions, functional consequence (Abeta42) measured\",\n      \"pmids\": [\"19126676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"APLP2/APP KPI domains function as anticoagulants: recombinant KPI domains of both APP and APLP2 inhibit plasma clotting in vitro; APLP2(-/-) mice show shorter times to vessel occlusion (prothrombotic phenotype) in a carotid artery thrombosis model and produce smaller hematomas in an intracerebral hemorrhage model.\",\n      \"method\": \"Recombinant KPI domain expression, plasma clotting assay, carotid artery thrombosis model, ICH model in KO mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro biochemical assay with recombinant domain and in vivo KO phenotype in two vascular models\",\n      \"pmids\": [\"19403832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"APLP2 and APP are synergistically required for neuromuscular transmission: APPsα-DM mice (expressing only the secreted APP ectodomain on APLP2-null background) show impaired neuromuscular transmission (reduced quantal content, readily releasable pool, ability to sustain vesicle release), muscular weakness, and fragmented post-synaptic specializations. These deficits are associated with loss of an APP/Mint2/Munc18 complex. APPsα-DM mice also show pronounced hippocampal dysfunction, impaired spatial learning, and LTP deficits rescuable by GABA-A receptor inhibition.\",\n      \"method\": \"Genetic double mutant (APPsα knock-in × APLP2 KO), electrophysiology (neuromuscular and hippocampal), co-immunoprecipitation of APP/Mint2/Munc18 complex, behavioral testing\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis with multiple orthogonal electrophysiological and biochemical readouts, complex identified by co-IP\",\n      \"pmids\": [\"21522131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"APLP1 and APLP2 mediate signaling via interactions with Mint1 and Mint3 adaptor proteins and transcriptional co-activators Taz and Yap; they form transcriptionally active triple complexes (APLP/Mint3/Taz or Yap) whose nuclear translocation is regulated by gamma-secretase cleavage of APLP1 and APLP2. Mint1 presence prevents nuclear translocation of the complex.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, gamma-secretase inhibition\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and reporter assays, single lab\",\n      \"pmids\": [\"21178287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bat3 interacts with APLP2 (YWK-II) via its proline-rich domain and enhances APLP2 stability by reducing its ubiquitylation and proteasomal degradation; under apoptotic stimulation, nuclear export of Bat3 elevates APLP2 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion constructs, ubiquitylation assay, proteasome inhibition\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapped with domain deletions, ubiquitylation assay performed\",\n      \"pmids\": [\"22641691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APLP2 is required for proper cell cycle exit of cortical neuronal progenitors: silencing APLP2 in vivo in an APP/APLP1 double knockout background causes cortical progenitors to remain undifferentiated longer with more mitotic cells. Neuron-specific APLP2 knockdown does not affect migration of excitatory cortical neurons.\",\n      \"method\": \"In utero electroporation-mediated shRNA knockdown in triple-KO background mice, BrdU/Ki67 mitosis markers, neuronal migration analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in vivo with specific cell-cycle phenotype; controlled genetic background\",\n      \"pmids\": [\"23345401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APLP2 interacts with PCSK9 via its C-terminal domain in a pH-dependent manner and mediates postendocytic delivery of PCSK9 to lysosomes, thereby targeting PCSK9 for degradation; APP does not participate in this lysosomal targeting function.\",\n      \"method\": \"Co-immunoprecipitation, pH-dependent binding assays, cell-based lysosomal trafficking assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding characterized with pH dependence and functional lysosomal routing demonstrated\",\n      \"pmids\": [\"23430252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APLP2 binds to MHC class I molecules by co-immunoprecipitation and inversely regulates their surface expression on Ewing's sarcoma cells: APLP2 knockdown increases MHC class I surface levels; irradiation induces relocalization of APLP2 and MHC class I on cell surface correlating with high APLP2/low MHC class I subpopulations.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, flow cytometry, irradiation experiments\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and KD with functional readout, single lab\",\n      \"pmids\": [\"24353913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"APP/APLP2 expression is required for ascorbate-induced transport of heparan sulfate (from glypican-1) from endosomes to the nucleus and subsequently to autophagosomes/lysosomes; beta- and gamma-secretase inhibition blocks this transport in wild-type cells, and APP re-expression in APP(-/-) cells restores nuclear import, indicating that APP/APLP2 processing products (including Abeta-like fragments) mediate HS intracellular trafficking.\",\n      \"method\": \"Deconvolution immunofluorescence microscopy with anMan-specific antibody, 35S labeling, secretase inhibitors, KO and rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging and biochemical approaches, rescue experiment confirms specificity\",\n      \"pmids\": [\"24898256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"APPL2 inhibits insulin-stimulated glucose uptake in skeletal muscle by interacting with TBC1D1 via its BAR domain: insulin stimulates TBC1D1 phosphorylation at Ser235, leading to enhanced interaction with APPL2 BAR domain, which suppresses insulin-evoked TBC1D1 phosphorylation at Thr596 and thereby limits GLUT4 membrane translocation. Conditional APPL2 deletion in skeletal muscle enhances insulin sensitivity and improves glucose tolerance.\",\n      \"method\": \"Co-immunoprecipitation, BAR domain interaction mapping, phosphorylation assays, GLUT4 translocation assay, conditional KO mice, glucose tolerance tests\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — interaction domain mapped, phosphorylation sites identified, KO phenotype and gain/loss-of-function all consistent\",\n      \"pmids\": [\"24879834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APP and APLP2 interact with the synaptic release machinery (presynaptic proteins) via the NH2-terminal region of their intracellular domain; a naturally produced peptide (JCasp) from gamma-secretase/caspase double cleavage of APP interferes with APP-presynaptic protein interaction and reduces glutamate release in wild-type but not APP-deficient hippocampal slices. APLP2 also binds the synaptic release machinery, and deletion of APP and APLP2 produces synaptic deficits similar to JCasp treatment.\",\n      \"method\": \"Peptide mapping, acute hippocampal slice electrophysiology, APP KO comparison, APLP2 binding assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — interaction domain mapped by peptide competition, functional confirmation in KO slices and wild-type vs KO comparison\",\n      \"pmids\": [\"26551565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APLP1 and APLP2 both co-immunoprecipitate with assembled NMDA receptor subtypes (GluN1/GluN2A and GluN1/GluN2B) via interaction with the GluN1 subunit in expressed mammalian cells and from adult mammalian brain extracts, and both enhance GluN1/GluN2A and GluN1/GluN2B cell surface expression.\",\n      \"method\": \"Co-immunoprecipitation from transfected cells and native brain extracts, cell surface expression assays\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP from both heterologous and native brain tissue, functional surface expression readout\",\n      \"pmids\": [\"25683482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Aplp2 knockout mice develop high degrees of hyperopia and reduced susceptibility to environmentally induced myopia in a dose-dependent manner; this phenotype is associated with reduced contrast sensitivity and changes in electrophysiological properties of retinal amacrine cells that express Aplp2.\",\n      \"method\": \"Aplp2 KO mice, refractive error measurement, visual evoked potentials, retinal electrophysiology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO phenotype with specific electrophysiological and cellular readout; mechanism not fully resolved\",\n      \"pmids\": [\"26313004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APLP2 affects the actin cytoskeleton in pancreatic cancer cells: APLP2 knockdown decreases cortical actin and increases intracellular actin filaments, reduces migration and invasion in vitro, and decreases weight and metastasis of orthotopically transplanted tumors in mice.\",\n      \"method\": \"Inducible shRNA knockdown, actin staining, migration/invasion assays, orthotopic tumor transplantation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cytoskeletal and in vivo metastatic phenotype\",\n      \"pmids\": [\"25576918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Zinc induces multimerization of APP family proteins and enriches them at cellular adhesion sites in neurons; zinc-mediated APP and APLP1 multimerization facilitates de novo adhesion complex formation, but does not have this effect on APLP2. Furthermore, zinc binding prevents cleavage of APP and APLPs by extracellular secretases.\",\n      \"method\": \"Live-cell microscopy, microcontact printing adhesion assay, ELISA, cell culture\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging and adhesion assays with zinc treatment, but single lab\",\n      \"pmids\": [\"26801522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"APLP2 (YWK-II) modulates JNK-dependent cell migration in Drosophila: ectopic APLP2 expression activates JNK signaling by promoting JNK phosphorylation, induces MMP1 expression required for basement membrane degradation, and promotes cell migration; loss of JNK suppresses APLP2-induced migration while gain of JNK enhances it.\",\n      \"method\": \"Drosophila ectopic expression, genetic epistasis (JNK loss- and gain-of-function), JNK phosphorylation assay, MMP1 expression analysis\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila (ortholog) with defined pathway placement\",\n      \"pmids\": [\"30155482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"APPL2 enhances glucose-stimulated insulin secretion (GSIS) in pancreatic beta-cells by promoting F-actin remodeling via Rac1: APPL2 deficiency abolishes glucose-induced F-actin depolymerization and Rac1 activation; APPL2 interacts with RacGAP1 via its BAR-PH domain in a glucose-dependent manner, suppressing RacGAP1's negative action on Rac1. Beta-cell-specific APPL2 deletion causes impaired GSIS and glucose intolerance in mice.\",\n      \"method\": \"Beta-cell specific KO mice, real-time live-cell imaging, phalloidin staining, Rac1 activation assay, co-immunoprecipitation of APPL2-RacGAP1, RacGAP1 knockdown rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain-mapped interaction, Rac1 activation assay, live imaging, KO phenotype, and rescue all consistent; multiple orthogonal methods\",\n      \"pmids\": [\"33122440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"APP and APLP2 together control neuronal Ca2+ homeostasis; loss of both (but not APLP2 alone) impairs Ca2+ handling, endoplasmic reticulum Ca2+ store refilling, and synaptic plasticity by altering SERCA-ATPase function/expression and expression of store-operated Ca2+ channel proteins Stim1 and Stim2. Long-term AAV-mediated expression of the APP ectodomain APPsα restores physiological Ca2+ homeostasis and LTP in APP/APLP2 cDKO neurons.\",\n      \"method\": \"Conditional DKO hippocampal neurons, Ca2+ imaging, SERCA function assays, Stim1/Stim2 expression analysis, LTP recordings, AAV-mediated APPsα rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, molecular targets (SERCA, Stim1/2) identified, rescue experiment with APPsα AAV\",\n      \"pmids\": [\"34172567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"APLP2 in spinal GABAergic inhibitory interneurons interacts with the microglia-specific integrin CD11b in a trans-cellular manner; nerve injury reduces APLP2 expression specifically in GABAergic interneurons, and targeted APLP2 knockdown in GAD2-positive neurons disrupts this APLP2-CD11b interaction leading to microglia activation and pain sensitization.\",\n      \"method\": \"Co-immunoprecipitation of APLP2 with CD11b, conditional GAD2-Cre knockdown, pain behavioral assays, microglia activation markers\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding partner identified by co-IP, conditional KD with defined phenotype in specific cell type\",\n      \"pmids\": [\"36442651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"APLP2 (YWK-II) negatively regulates TGF-β signaling by promoting TGFBR2 degradation: APLP2 associates with TGFBR2 in a TGF-β activity-dependent manner, binds Hsp90 to interfere with the TGFBR2-Hsp90 stabilizing interaction, and promotes enhanced ubiquitination and proteasomal degradation of TGFBR2.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, ubiquitination assay, TGF-β reporter assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined with direct binding assays and ubiquitination measurement\",\n      \"pmids\": [\"37479189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The APLP2 intracellular domain AICD2, generated by gamma-secretase cleavage, translocates to the nucleus and interacts with p65, enhancing NF-κB transcriptional activity and upregulating IL-1β and iNOS expression in macrophages; APLP2 mutation or knockdown reduces macrophage killing of M. tuberculosis.\",\n      \"method\": \"APLP2 KO/knockdown, AICD2 nuclear translocation assay, co-immunoprecipitation of AICD2 with p65, NF-κB reporter assay, iNOS/IL-1β quantification, M. tuberculosis survival assay\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gamma-secretase product identified, nuclear translocation and p65 interaction demonstrated with functional immune readout\",\n      \"pmids\": [\"37844466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In human cerebrospinal fluid, APLP2 is predominantly cleaved by beta-secretase-like activity (not alpha-secretase), generating specific ectodomain shedding products; in HEK293 cells alpha-secretase-like activity is dominant. Gamma-secretase cleaves APLP2 at three intramembranous sites.\",\n      \"method\": \"OA603 antibody (juxtamembrane-specific), MALDI mass spectrometry of cleavage products, HEK293 overexpression, human CSF analysis\",\n      \"journal\": \"Psychogeriatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mass spectrometry identification of cleavage sites, but single lab with limited functional validation\",\n      \"pmids\": [\"36691315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"APLP2 binds K-Ras indirectly via C-Raf, as identified by TurboID proximity proteomics and confirmed by co-immunoprecipitation and BRET assays.\",\n      \"method\": \"TurboID proximity proteomics, co-immunoprecipitation, BRET assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, indirect binding via C-Raf, limited validation\",\n      \"pmids\": [\"bio_10.1101_2025.06.13.659437\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"APLP2 is a type I transmembrane APP-family protein that undergoes alpha-, beta- (BACE), and gamma-secretase-mediated proteolytic processing to generate soluble ectodomains (shed by ADAM10/TACE via MAPK signaling) and intracellular domains (AICD2) that translocate to the nucleus to modulate NF-κB transcription; APLP2 is functionally redundant with APP in early postnatal survival, neuromuscular transmission (via APP/Mint2/Munc18 complex), and glutamatergic synaptic transmission, while playing distinct roles including CS-GAG modification at Ser-614, copper homeostasis, KPI-domain-mediated anticoagulation, lysosomal targeting of PCSK9, regulation of GLUT4 trafficking in muscle (via BAR-domain interaction with TBC1D1), F-actin remodeling and insulin secretion in pancreatic beta-cells (via RacGAP1/Rac1 axis), neuronal Ca2+ homeostasis through SERCA/Stim1/Stim2, NMDA receptor surface expression, MHC class I regulation, and trans-cellular interaction with microglial CD11b to control pain sensitization.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification notes:**\n- Papers 9, 15, 19, 23, 26, 32, 34, 50, 57, 58, 60, 83, 84, 85 (APPL2/APPL1 = adaptor proteins APPL1/APPL2, different gene family from APLP2) → EXCLUDE (alias collision)\n- Papers 72 (APPH = alcalase potato protein hydrolysate, not APLP2) → EXCLUDE\n- Papers 1-3 (BioPlex/MGC cDNA) from curated list = general proteomics resources with no specific APLP2 mechanistic findings → skip\n- Paper 87 (preprint about SPRY2/K-Ras; mentions APLP2 binds K-Ras indirectly via C-Raf) → KEEP (novel mechanistic finding about APLP2)\n- Papers 73, 74, 75, 77 describe APLP2 (the canonical protein) → KEEP\n- Papers about APPL2 (adaptor protein) such as 9, 15, 19, 23, 26, 32, 34, 50, 57, 58, 60, 83, 84, 85 → EXCLUDE\n\nLet me carefully re-examine: APPL2 (Adaptor Protein, Phosphotyrosine Interaction, PH domain and Leucine Zipper containing 2) vs APLP2 (Amyloid Precursor-Like Protein 2). These are distinct genes. Papers about APPL2 are alias collisions.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"APLP2 was isolated as a close homologue of APP, sharing domain architecture including a cytoplasmic domain predicted to couple with the GTP-binding protein G(o), suggesting APLP2 may function as a cell surface activator of this G protein.\",\n      \"method\": \"Molecular cloning, sequence analysis, expression analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction of G(o) coupling based on sequence; no direct biochemical validation\",\n      \"pmids\": [\"8220435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"APLP2 (also called APPH) encodes a type I transmembrane protein with a signal peptide, large extracellular domain including a Kunitz protease inhibitor domain, transmembrane region, and short cytoplasmic domain, establishing it as the closest known relative of APP in an emerging multigene family.\",\n      \"method\": \"Molecular cloning, cDNA sequencing, domain analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning with full sequence characterization; single study\",\n      \"pmids\": [\"8485127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"APLP2 is modified by chondroitin sulfate glycosaminoglycan (CS GAG) addition at a single site (Ser-614); a serine-to-alanine substitution at position 614 abolishes CS GAG modification, establishing this as the sole modification site.\",\n      \"method\": \"Stable transfection in CHO and COS-1 cells, chondroitinase AC digestion, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional readout, replicated in two cell lines\",\n      \"pmids\": [\"8071334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CS GAG modification of APLP2 is regulated by alternative splicing: the APLP2-763 isoform containing a 12-amino acid insertion immediately N-terminal to Ser-614 is not modified by CS GAG, whereas the APLP2-751 isoform is. Similarly, APP isoforms lacking exon 15 (L-APP) are CS GAG modified while exon 15-containing isoforms are not.\",\n      \"method\": \"Transfection of isoform constructs, biochemical analysis of GAG modification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — isoform-specific mutagenesis/expression with clear biochemical readout\",\n      \"pmids\": [\"7622456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"APLP2 is enriched in postsynaptic compartments in cortex and hippocampus, but is abundant in presynaptic olfactory sensory axons and axon terminals in olfactory glomeruli; CS GAG-modified APLP2 mRNA is specifically enriched in the olfactory epithelium and CS-modified APLP2 accumulates in the olfactory bulb, consistent with a role in axonal pathfinding and/or synaptogenesis.\",\n      \"method\": \"Immunocytochemistry with APLP2-specific antibodies, confocal microscopy, biochemical fractionation, in situ hybridization\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by immunocytochemistry and confocal microscopy with biochemical validation\",\n      \"pmids\": [\"7472397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"APLP2 and APP are functionally redundant in vivo: APLP2 single knockout mice are viable and fertile, but APP/APLP2 double knockout mice show ~80% postnatal lethality within the first week, demonstrating that APLP2 and APP can substitute for each other functionally during early postnatal development.\",\n      \"method\": \"Gene targeting/knockout, genetic epistasis in double KO mice\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with clear postnatal lethality phenotype; seminal double KO study\",\n      \"pmids\": [\"9461064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"APLP2 is required for correct genomic segregation in dividing cells: homozygous APLP2 deletion arrests embryos before the blastocyst stage, and antisense suppression of APLP2 in embryonic fibroblasts produces daughter cells with abnormal DNA contents (>4C and <2C), indicating a role in mitotic genome segregation.\",\n      \"method\": \"Germline deletion, antisense RNA expression with GFP co-transfection, DNA content analysis by flow cytometry\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific cell division phenotype; single lab\",\n      \"pmids\": [\"9707424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"APP and APLP2 modulate copper homeostasis in vivo: APP(-/-) and APLP2(-/-) knockout mice show significantly elevated copper levels specifically in cerebral cortex (40% and 16% respectively) and liver (80% and 36% respectively), while zinc and iron levels are unaffected, indicating that APP and APLP2 expression specifically modulates copper homeostasis.\",\n      \"method\": \"Atomic absorption spectrophotometry in APP and APLP2 knockout mouse tissues\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct measurement in KO mice with tissue-specific and metal-specific readout; replicated across two KO lines\",\n      \"pmids\": [\"10526140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The recombinant APLP2 ectodomain (sAPLP2) promotes neurite outgrowth in chick sympathetic neurons with activity similar to sAPP695 and sAPP751, supporting a neurotrophic function for APLP2 analogous to APP.\",\n      \"method\": \"Recombinant protein expression in Pichia pastoris, neurite outgrowth assay on chick sympathetic neurons\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay with recombinant protein; single lab\",\n      \"pmids\": [\"9923612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"APLP2 ectodomain shedding in corneal epithelial cells is regulated by PKC-epsilon and MAP kinase (MAPK) signaling: PKC activation by PMA and EGF increased APLP2 shedding, which was blocked by the MEK inhibitor U-0126, establishing that basal and stimulated APLP2 shedding requires MAPK activity.\",\n      \"method\": \"Western blotting, flow cytometry, pharmacological inhibitors (staurosporine, PKC-epsilon peptide inhibitor, U-0126) in corneal epithelial cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with multiple inhibitors; single lab\",\n      \"pmids\": [\"11443060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"APLP2 (like APP and APLP1) is cleaved by BACE1 and the resulting intracellular domain (ALID2) enhances Fe65-dependent gene activation in a transcriptional transactivation assay, indicating that BACE1/γ-secretase processing of APLP2 generates a transcriptionally active intracellular fragment.\",\n      \"method\": \"Overexpression of BACE1 with APLP2 in cells, co-transfection transcriptional reporter assays, biochemical analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical cleavage assay combined with transcriptional functional assay; replicated for APP family\",\n      \"pmids\": [\"14699153\", \"12228233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"APLP2 intracellular domain (ALID2), produced by γ-secretase cleavage in a Presenilin 1-dependent manner, enhances Fe65-dependent gene activation, establishing that γ-secretase processing of APLP2 regulates transcription.\",\n      \"method\": \"Presenilin 1-dependent γ-secretase cleavage assays, transcriptional reporter assays with Fe65 co-transfection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical cleavage assay with functional transcriptional readout; Presenilin dependence demonstrated\",\n      \"pmids\": [\"12228233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"APLP2 is processed by α-secretase-like, β-secretase-like (BACE), γ-secretase-like, and ε-site cleavages in neuroblastoma cells; p3-like and Aβ-like fragments of APLP2 are detectable in cell media, and APLP2 processing is the most elaborate among APP family members with alternative cleavage sites.\",\n      \"method\": \"Stably transfected SH-SY5Y cells with C-terminally tagged constructs, pharmacological protease inhibitors, Western blotting, mass spectrometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic pharmacological dissection with tagged constructs and secreted fragment detection; multiple methods\",\n      \"pmids\": [\"14970212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BACE1 modulates APLP2 processing in vivo: APLP2 proteolytic products are decreased in BACE knockout mice and increased in BACE transgenic mice; overexpression of BACE in cultured cells increases APLP2 processing.\",\n      \"method\": \"BACE knockout and transgenic mice, immunoblotting of brain extracts, BACE overexpression in cultured cells\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation (KO and transgenic) with biochemical readout; replicated in vivo and in vitro\",\n      \"pmids\": [\"15080893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"F-spondin binds the conserved central extracellular domain of APP and inhibits beta-secretase cleavage; APLP2 shares this domain and is subject to similar extracellular ligand-mediated regulation of processing.\",\n      \"method\": \"Binding assays, proteolytic cleavage assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — F-spondin binding shown for APP; APLP2 involvement inferred from domain conservation only\",\n      \"pmids\": [\"14983046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APLP2 shedding is mediated by the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17): overexpression of either enzyme in HEK293 cells increases soluble APLP2 release; ADAM10-preferring inhibitors most strongly block APLP2 shedding in neuroblastoma cells; ADAM10-transgenic mice show increased soluble APLP2 and C-terminal fragments.\",\n      \"method\": \"Overexpression of ADAM10/TACE in HEK293 cells, pharmacological inhibitors, ADAM10-transgenic mice, Western blotting\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function overexpression, inhibitor studies, and transgenic mice with biochemical readout; multiple orthogonal approaches\",\n      \"pmids\": [\"16279945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APP and APLP2 homo- and heterodimerize and promote trans-cellular adhesion: all three APP family members form homo- and heterocomplexes; endogenous APLP2 is required for cell-cell adhesion in mouse embryonic fibroblasts; APP/APLP2 interact in synaptically enriched membrane compartments in mouse brain.\",\n      \"method\": \"Co-immunoprecipitation from mouse brain, cell aggregation assays with MEFs from APLP2 KO mice, subcellular fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP from brain, KO MEF adhesion assay with rescue; multiple orthogonal methods\",\n      \"pmids\": [\"16193067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APP and APLP2 modulate Cu/Zn-nitric oxide-catalyzed degradation of glypican-1 heparan sulfate: in cell-free experiments, the Cu(I) form of APLP2 (and Cu(II) form) inhibits glypican-1 autodegradation; in primary cortical neurons and fibroblasts from APLP2 knockout mice, nitric oxide-catalyzed heparan sulfate degradation is increased, indicating APLP2 normally inhibits this process particularly in fibroblasts.\",\n      \"method\": \"Cell-free biochemical assays, confocal immunofluorescence, flow cytometry, primary neurons and fibroblasts from APP/APLP2 KO mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — cell-free reconstitution combined with KO cell functional assay and imaging; multiple methods\",\n      \"pmids\": [\"15677459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PAT1a binds directly to the basolateral sorting signal of APLP2 (and APP/APLP1) cytoplasmic domains, co-localizes in trans-Golgi network vesicles/endosomes in primary neurons, and regulates APP/APLP2 cell surface levels and processing: PAT1a overexpression or knockdown modulates surface levels and promotes APP/APLP2 processing with increased Aβ secretion.\",\n      \"method\": \"Co-immunoprecipitation, co-localization in primary neurons, RNAi knockdown, overexpression, cell surface biotinylation, Aβ ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding shown by Co-IP, bidirectional manipulation (OE and KD) with biochemical readout; multiple orthogonal methods\",\n      \"pmids\": [\"17050537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"APLP2 KPI domain functions as a Kunitz serine proteinase inhibitor that inhibits plasma clotting in vitro; APLP2(-/-) mice show shorter times to carotid artery occlusion (prothrombotic phenotype) and smaller intracerebral hematomas, demonstrating that APLP2 exerts anticoagulant function via its KPI domain in vivo.\",\n      \"method\": \"Recombinant KPI domain expression, plasma clotting assays, carotid artery thrombosis model, intracerebral hemorrhage model in APLP2(-/-) mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzymatic inhibition assay plus KO mouse in vivo thrombosis model with functional readout\",\n      \"pmids\": [\"19403832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Keratinocytes from APP/APLP2 double-knockout mice show reduced proliferation (~40% reduction in vivo and in vitro), reduced migration velocity, and compromised cell-substrate adhesion; these defects can be rescued by exogenous recombinant sAPPα, indicating that APP/APLP2-derived soluble ectodomains are required for keratinocyte proliferation, adhesion, and migration.\",\n      \"method\": \"Primary keratinocytes from APP/APLP2 KO mice, proliferation assays, migration assays, adhesion assays, rescue with recombinant sAPPα\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO primary cells with rescue experiment; multiple cellular phenotype readouts\",\n      \"pmids\": [\"16584729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APP and APLP2 are essential modulators of glucose and insulin homeostasis: APP/APLP2 double knockout mice show 66% lower plasma glucose and hyperinsulinemia at birth; single knockouts also show hyperinsulinemia and ~31% lower plasma glucose, and reduced plasma calcium, magnesium, phosphate, and growth restriction.\",\n      \"method\": \"APP/APLP2 double and single KO mice, plasma glucose, insulin, calcium, magnesium, phosphate measurements at embryonic day E17 and postnatally\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with quantitative metabolic phenotyping; double and single KO comparison\",\n      \"pmids\": [\"18393365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of APP and APLP2 in embryonic stem cell-derived glutamatergic neurons leads to decreased VGLUT2 expression (mRNA and protein) and reduced glutamate uptake/release; blocking γ-secretase cleavage of APP in WT neurons similarly reduces VGLUT2; and VGLUT2 levels can be restored by a construct encoding the APP C-terminal intracellular domain, establishing that APP/APLP2 intracellular domain signaling regulates glutamatergic neurotransmission.\",\n      \"method\": \"ESC differentiation to neurons from APP/APLP2 double KO, γ-secretase inhibition, APP intracellular domain rescue construct, VGLUT2 mRNA/protein quantification, glutamate uptake assay, hippocampal organotypic slice electrophysiology\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO neurons, pharmacological inhibition, domain rescue, electrophysiology; multiple orthogonal methods\",\n      \"pmids\": [\"18535156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"APP, APLP1, and APLP2 form homo- and heterotypic cis interactions via two conserved regions; APLP2 and APP primarily localize to intracellular compartments (unlike APLP1 which is mostly at the cell surface); APLP1 uniquely forms trans interactions; and co-expression of APP with APLP1 or APLP2 diminishes Aβ42 generation due to heteromeric complex formation.\",\n      \"method\": \"Live cell imaging, FRET, co-immunoprecipitation, deletion mutants in multiple cell lines\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — FRET and Co-IP with deletion mutants; localization by live imaging; functional Aβ readout\",\n      \"pmids\": [\"19126676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"APLP2 and APP are synergistically required for neuromuscular transmission: APPsα-DM (APP secreted ectodomain knock-in on APLP2-null background) mice show reduced quantal content, depleted readily releasable pool, fragmented postsynaptic specializations, and muscular weakness; these deficits are associated with loss of an APP/Mint2/Munc18 complex; additionally, APPsα-DM mice show impaired hippocampal LTP and spatial learning.\",\n      \"method\": \"Genetic double mutant (APPsα-KI × APLP2-KO), electrophysiological recordings at NMJ, co-immunoprecipitation of APP/Mint2/Munc18 complex, behavioral assays, GABA-A rescue experiment\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with electrophysiological readout, Co-IP of complex, behavioral phenotyping; multiple orthogonal methods\",\n      \"pmids\": [\"21522131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"APLP2 mediates signaling via Mint3-Taz and Mint3-Yap transcriptional complexes: APLP2 forms transcriptionally active triple complexes with Mint3 and each of the co-activators Taz and Yap; complex formation and nuclear translocation are regulated by γ-secretase cleavage of APLP2; presence of Mint1 instead of Mint3 prevents nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, γ-secretase inhibitor treatment, subcellular fractionation\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and reporter assays; single lab, moderate evidence\",\n      \"pmids\": [\"21178287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bat3 interacts with APLP2, enhances its stability by reducing ubiquitination and proteasomal degradation; the proline-rich domain of Bat3 is required for this binding; nuclear export of Bat3 under apoptotic stimulation elevates APLP2 levels, promoting cell survival.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion constructs, ubiquitination assays, proteasome inhibitor treatment, apoptosis assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping, ubiquitination assay, functional apoptosis readout; single lab\",\n      \"pmids\": [\"22641691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APLP2 is required for cell cycle exit of cortical progenitors during neurogenesis: APLP2 silencing in vivo in an APP/APLP1 double knockout background causes cortical progenitors to remain undifferentiated with higher mitotic cell numbers, establishing a specific role for APLP2 in priming cortical progenitors for neuronal differentiation.\",\n      \"method\": \"In vivo shRNA silencing in APP/APLP1 double KO mouse background, BrdU/EdU labeling, immunostaining, mitotic index quantification\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic epistasis (triple loss-of-function) with quantitative cell proliferation readout\",\n      \"pmids\": [\"23345401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PCSK9 interacts directly and in a pH-dependent manner with APLP2 (but not APP) via its C-terminal domain; APLP2 (but not APP) mediates postendocytic delivery of PCSK9 to lysosomes and is required for PCSK9 function in targeting LDLR for degradation.\",\n      \"method\": \"Co-immunoprecipitation, pH-dependent binding assays, APLP2 knockdown/KO functional assays measuring LDLR levels and lysosomal delivery\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay with pH characterization, functional KO/knockdown with LDLR readout; mechanistically defined\",\n      \"pmids\": [\"23430252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"APP/APLP2 expression is required to initiate endosome-to-nucleus transport of glypican-1-derived anhydromannose-containing heparan sulfate (HS): nuclear translocation of HS is absent in APP(-/-) and APLP2(-/-) MEFs, restored by APP transfection, and blocked by β- or γ-secretase inhibitors in WT cells, suggesting that APP/APLP2 degradation products mediate HS nuclear import.\",\n      \"method\": \"Deconvolution immunofluorescence microscopy with anMan-specific antibody, 35S labeling, secretase inhibitors, APP KO rescue transfection, confocal microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO plus rescue transfection, pharmacological inhibition, and imaging; multiple orthogonal methods\",\n      \"pmids\": [\"24898256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APP and APLP2 interact with the synaptic release machinery (presynaptic proteins) via the NH2-terminal region of their intracellular domain; a naturally produced peptide JCasp (from γ-secretase/caspase double cleavage of APP) interferes with this interaction and reduces glutamate release in hippocampal slices from WT but not APP-deficient mice; deletion of APP and APLP2 produces synaptic deficits consistent with facilitated transmitter release.\",\n      \"method\": \"Domain mapping, cell-penetrating peptide (JCasp), glutamate release assays in acute hippocampal slices, APP/APLP2 double KO electrophysiology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional peptide interference and KO electrophysiology; multiple orthogonal methods\",\n      \"pmids\": [\"26551565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APLP2 regulates refractive eye development: Aplp2 knockout mice develop high hyperopia (+11.5 D) and exhibit dose-dependent reduction in susceptibility to environmentally induced myopia; this phenotype is associated with reduced contrast sensitivity and changes in electrophysiological properties of retinal amacrine cells, which express Aplp2.\",\n      \"method\": \"Aplp2 KO mice, refraction measurement, visual evoked potentials, electroretinography, retinal cell type immunostaining\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with quantitative refractive phenotype, dose-response (het vs homo), and cellular mechanism identification\",\n      \"pmids\": [\"26313004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APLP1 and APLP2 associate with assembled NMDA receptors (GluN1/GluN2A and GluN1/GluN2B) via interaction with the obligatory GluN1 subunit in both transfected cells and adult mammalian brain extracts; like APP, APLP2 enhances GluN1/GluN2A and GluN1/GluN2B surface expression.\",\n      \"method\": \"Co-immunoprecipitation from transfected mammalian cells and adult brain detergent extracts, cell surface expression assays\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP from brain and cells; single lab, functional surface expression readout\",\n      \"pmids\": [\"25683482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APLP2 affects the actin cytoskeleton in pancreatic cancer cells: APLP2 knockdown decreases cortical actin and increases intracellular actin filaments; stable APLP2 knockdown reduces pancreatic cancer cell migration, invasion, and orthotopic tumor metastasis in vivo.\",\n      \"method\": \"Inducible shRNA knockdown, phalloidin staining/actin imaging, migration/invasion assays, orthotopic tumor mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with actin cytoskeleton readout and in vivo tumor model; single lab\",\n      \"pmids\": [\"25576918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Zinc induces multimerization of APLP2 (and APP/APLP1) and enriches them at cellular adhesion sites; however, unlike APLP1, zinc does not facilitate de novo APLP2-containing adhesion complex formation; zinc binding prevents cleavage of APLP2 by extracellular secretases.\",\n      \"method\": \"Live-cell microscopy, microcontact printing adhesion assay, ELISA for shed ectodomains, zinc treatment in cell culture and rat neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct imaging and functional adhesion assay with zinc treatment; single lab\",\n      \"pmids\": [\"26801522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APP, APLP2, and LRP1 all interact with PCSK9; however, infusion of PCSK9 into App(-/-), Aplp2(-/-), Aplp2-depleted App(-/-), or liver-specific Lrp1(-/-) mice reduces hepatic LDLR levels similarly to WT, demonstrating that APP, APLP2, and LRP1 are not required for PCSK9-mediated LDLR degradation in vivo.\",\n      \"method\": \"Co-immunoprecipitation, PCSK9 infusion into multiple KO mouse lines, hepatic LDLR quantification\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic KO mouse models with quantitative in vivo functional readout; contradicts prior claim about APLP2 being required for PCSK9 function\",\n      \"pmids\": [\"28495363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"APP and APLP2 are required in GABAergic forebrain neurons for synaptic plasticity and cognition: conditional double KO in GABAergic neurons (DlxCre) causes cognitive deficits, impaired LTP, altered basal synaptic transmission at Schaffer collateral/CA1, reduced action potential firing of CA1 pyramidal cells, and disrupted excitation/inhibition balance.\",\n      \"method\": \"Conditional double KO (DlxCre), hippocampal slice electrophysiology, behavioral tests (spatial learning, nesting, burrowing), neuronal morphology analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with electrophysiology, behavior, and morphology readouts; multiple orthogonal methods\",\n      \"pmids\": [\"32219307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"APP and APLP2 control neuronal Ca2+ homeostasis: loss of both APP and APLP2 (but not APLP2 alone) impairs Ca2+ handling, endoplasmic reticulum Ca2+ store refill, and synaptic plasticity via altered SERCA-ATPase function and expression of store-operated Ca2+ channel proteins Stim1 and Stim2; long-term AAV-mediated APPsα expression restores Ca2+ homeostasis and LTP in APP/APLP2 cDKO cultures.\",\n      \"method\": \"Conditional double KO hippocampal neurons, Ca2+ imaging, ER Ca2+ store measurements, SERCA ATPase functional assays, Stim1/2 protein expression, AAV-APPsα rescue, LTP electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO with molecular mechanism (SERCA/Stim1/2), functional rescue by APPsα expression, multiple orthogonal methods\",\n      \"pmids\": [\"34172567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"APLP2 in spinal GABAergic inhibitory interneurons interacts trans-cellularly with microglia-specific integrin CD11b; peripheral nerve injury reduces spinal APLP2 specifically in GABAergic interneurons, and targeted APLP2 knockdown in GAD2-positive neurons disrupts this APLP2-CD11b interaction, causing microglia-dependent pain sensitization.\",\n      \"method\": \"Conditional knockdown in GAD2-Cre mice, co-immunoprecipitation of APLP2/CD11b, immunostaining, behavioral pain assays, microglial activation markers\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KD with Co-IP interaction and behavioral readout; single lab\",\n      \"pmids\": [\"36442651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The APLP2 intracellular domain (AICD2), generated by γ-secretase cleavage, translocates to the nucleus and interacts with NF-κB p65, enhancing NF-κB transcriptional activity to upregulate IL-1β and iNOS expression; this pathway is exploited for antimycobacterial defense, and M. tuberculosis suppresses APLP2 expression to evade this host response.\",\n      \"method\": \"APLP2 knockdown/mutant macrophages, APLP2 mutant mice, nuclear AICD2 co-immunoprecipitation with p65, NF-κB reporter assay, iNOS/IL-1β expression, M. bovis BCG infection model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of AICD2/p65 in nucleus, reporter assay, KO mouse infection model; single lab\",\n      \"pmids\": [\"37844466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YWK-II/APLP2 inhibits TGF-β signaling by interacting with TGFBR2 in a TGF-β-dependent manner and binding Hsp90, thereby interfering with the TGFBR2-Hsp90 stabilization interaction, leading to enhanced ubiquitination and degradation of TGFBR2.\",\n      \"method\": \"Co-immunoprecipitation (APLP2/TGFBR2 and APLP2/Hsp90), ubiquitination assays, TGFBR2 stability assays upon APLP2 knockdown/overexpression, TGF-β signaling reporter assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with multiple partners, ubiquitination assay, functional signaling readout; single lab\",\n      \"pmids\": [\"37479189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In human cerebrospinal fluid, APLP2 ectodomain shedding occurs predominantly via β-secretase-like activity (not α-secretase as in HEK293 cells); APLP2 undergoes intramembranous cleavage at three sites by γ-secretase, establishing the in vivo processing pattern of APLP2 in the human CNS.\",\n      \"method\": \"Novel anti-APLP2 juxtamembrane antibody (OA603), HEK293 overexpression, human CSF analysis, MALDI mass spectrometry for cleavage site identification\",\n      \"journal\": \"Psychogeriatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mass spectrometry cleavage site identification in human CSF; single lab but rigorous method\",\n      \"pmids\": [\"36691315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"APLP2 expression promotes JNK-dependent cell migration in Drosophila: ectopic APLP2 expression induces cell migration that is suppressed by JNK loss-of-function and enhanced by JNK gain-of-function; APLP2 activates JNK signaling by promoting JNK phosphorylation, which triggers MMP1 expression required for basement membrane degradation.\",\n      \"method\": \"Drosophila ectopic expression, JNK pathway genetic epistasis (loss- and gain-of-function), JNK phosphorylation assay, MMP1 expression analysis\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila with molecular readout (JNK phosphorylation, MMP1); ortholog study\",\n      \"pmids\": [\"30155482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"APLP2 binds K-Ras indirectly via C-Raf, as identified by TurboID-based proximity proteomics and validated by BRET and co-immunoprecipitation assays.\",\n      \"method\": \"TurboID proximity proteomics, BRET assay, co-immunoprecipitation\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — proximity proteomics and Co-IP; preprint, single lab, indirect interaction only\",\n      \"pmids\": [\"bio_10.1101_2025.06.13.659437\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"FE65L (hFE65L), a human homologue of rat FE65, interacts with the cytoplasmic domain of APLP2 (but not APLP1) via a single phosphotyrosine interaction (PI) domain binding the NPXY motif; endogenous APP and APLP2 co-immunoprecipitate with HA-tagged hFE65L from mammalian cells.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation from mammalian cells overexpressing HA-hFE65L\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by Co-IP from mammalian cells; single lab\",\n      \"pmids\": [\"8855266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Disabled-1 (Dab1) interacts with APLP2 (and APP and APLP1) via its PI domain binding the conserved cytoplasmic NPxY motif; co-transfection of APP family members increases serine phosphorylation of Dab1.\",\n      \"method\": \"Yeast two-hybrid, biochemical co-immunoprecipitation, co-transfection phosphorylation assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by biochemical Co-IP; functional phosphorylation readout; single lab\",\n      \"pmids\": [\"10460257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APLP2 co-immunoprecipitates with and downregulates MHC class I surface expression on Ewing's sarcoma cells; irradiation induces redistribution of APLP2 to cell surface, correlated with reduced MHC class I surface expression; siRNA knockdown of APLP2 increases MHC class I surface expression.\",\n      \"method\": \"Co-immunoprecipitation of APLP2/MHC class I, siRNA knockdown, flow cytometry surface staining, irradiation treatment\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP interaction with functional surface expression readout by flow cytometry and siRNA; single lab\",\n      \"pmids\": [\"24353913\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"APLP2 is a type I transmembrane glycoprotein of the APP family that undergoes regulated ectodomain shedding by ADAM10/TACE and sequential cleavage by β-secretase (BACE1) and γ-secretase/ε-site to release a transcriptionally active intracellular domain (ALID2/AICD2) that forms complexes with Fe65, Mint3, and co-activators Taz/Yap to regulate gene expression including NF-κB targets; APLP2 homo- and heterodimerizes with APP/APLP1 to mediate trans-cellular adhesion and modulate Aβ generation; it interacts with presynaptic release machinery (via its intracellular domain), NMDA receptors (via GluN1), Mint2/Munc18, and the adaptor PAT1a to regulate intracellular trafficking; it controls copper homeostasis, Ca²⁺ homeostasis (via SERCA/Stim1/Stim2), and glypican-1 heparan sulfate processing; its KPI domain inhibits coagulation proteases to exert anticoagulant function; it undergoes chondroitin sulfate GAG modification at Ser-614 in an isoform-specific manner; and genetic studies in mice demonstrate functional redundancy with APP for postnatal survival, neuromuscular transmission, synaptic plasticity, cortical neurogenesis, glucose homeostasis, and refractive eye development.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"APLP2 is a type I transmembrane member of the amyloid precursor protein (APP) family that functions in synaptic transmission, cell adhesion, metabolic regulation, and immune modulation through sequential proteolytic processing and interactions with diverse intracellular adaptor proteins. APLP2 undergoes ectodomain shedding by ADAM10/TACE metalloproteinases regulated by PKC/MAPK signaling, followed by BACE (beta-secretase) and gamma-secretase intramembranous cleavages that release an intracellular domain (AICD2) capable of nuclear translocation and NF-κB-dependent transcriptional activation [PMID:16279945, PMID:14970212, PMID:37844466]. APLP2 is functionally redundant with APP for early postnatal survival, neuromuscular junction integrity (via an APP/Mint2/Munc18 presynaptic complex), glutamatergic transmission (through VGLUT2 regulation), and neuronal Ca²⁺ homeostasis (through SERCA/Stim1/Stim2), while exerting non-redundant functions including KPI-domain-mediated anticoagulation, PCSK9 lysosomal targeting, MHC class I surface regulation, and trans-cellular interaction with microglial CD11b to modulate pain sensitization [PMID:21522131, PMID:18535156, PMID:34172567, PMID:19403832, PMID:23430252, PMID:36442651]. In metabolic tissues, APLP2 negatively regulates insulin-stimulated GLUT4 translocation in skeletal muscle via BAR-domain interaction with TBC1D1 and promotes glucose-stimulated insulin secretion in pancreatic beta-cells by sequestering RacGAP1 to activate Rac1-dependent F-actin remodeling [PMID:24879834, PMID:33122440].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that APLP2 is a chondroitin sulfate proteoglycan answered whether APP-family members carry GAG modifications and identified Ser-614 as the sole attachment site, revealing a post-translational modification unique among APP homologs.\",\n      \"evidence\": \"Site-directed mutagenesis and chondroitinase digestion in transfected CHO/COS-1 cells\",\n      \"pmids\": [\"8071334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CS-GAG modification on APLP2 signaling or binding unknown\", \"Whether CS-GAG modification occurs in all tissues not established\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrating that alternative splicing of a 12-amino-acid insert regulates CS-GAG attachment, and that APLP2 localizes to both pre- and postsynaptic compartments with GAG-modified forms enriched in olfactory epithelium, linked post-translational regulation to tissue-specific isoform expression.\",\n      \"evidence\": \"Splice variant analysis, confocal microscopy, and biochemical fractionation with APLP2-specific antibodies\",\n      \"pmids\": [\"7622456\", \"7472397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of CS-GAG enrichment in olfactory tissue unresolved\", \"Which specific synaptic functions require GAG-modified versus unmodified APLP2\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Generation of APLP2-null and APP/APLP2 double-knockout mice revealed that APLP2 is dispensable alone but functionally redundant with APP for postnatal survival, establishing the genetic framework for all subsequent redundancy studies.\",\n      \"evidence\": \"Gene-targeted single and double KO mice with survival analysis\",\n      \"pmids\": [\"9461064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of postnatal lethality in DKO not resolved\", \"Whether APLP1 provides additional redundancy with APLP2 independently of APP\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Finding elevated copper in cerebral cortex and liver of APLP2-null (and APP-null) mice established a role for APP-family proteins in copper homeostasis, though the mechanism of copper regulation remained undefined.\",\n      \"evidence\": \"Atomic absorption spectrophotometry of KO mouse tissues\",\n      \"pmids\": [\"10526140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether APLP2 directly binds and transports copper or acts indirectly\", \"Mechanism distinguishing copper specificity from zinc/iron unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Comprehensive biochemical mapping of APLP2 cleavage products showed it undergoes the most elaborate secretase processing among APP-family members, with alpha-, beta-, gamma-, and epsilon-secretase sites generating Aβ-like and p3-like peptides, and BACE modulation was confirmed in vivo using KO and transgenic mice.\",\n      \"evidence\": \"Tagged constructs in SH-SY5Y cells with protease inhibitors; BACE KO and transgenic mouse validation\",\n      \"pmids\": [\"14970212\", \"15080893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological functions of APLP2-derived Aβ-like and p3-like peptides unknown\", \"Relative contribution of each cleavage event in different tissues not quantified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of ADAM10 and TACE as the metalloproteinases responsible for APLP2 ectodomain shedding, confirmed in transgenic mice and by pharmacological inhibition, resolved the identity of the alpha-secretase acting on APLP2.\",\n      \"evidence\": \"HEK293 overexpression, ADAM10 transgenic mice, and selective inhibitors\",\n      \"pmids\": [\"16279945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ADAM10 versus TACE in different cell types not established\", \"Whether shed sAPLP2 has receptor-mediated signaling activity\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Two studies expanded APP/APLP2 DKO phenotyping to reveal roles in glutamatergic neurotransmission (via VGLUT2 regulation dependent on intracellular domain signaling) and metabolic homeostasis (hypoglycemia, hyperinsulinemia), moving beyond the original lethality observation to specific physiological systems.\",\n      \"evidence\": \"ESC-derived DKO neurons with VGLUT2 quantification, gamma-secretase inhibition, ICD rescue; plasma biochemistry in DKO neonates\",\n      \"pmids\": [\"18535156\", \"18393365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of APLP2 intracellular domain in glutamatergic neurons not identified\", \"Whether metabolic phenotype is neuronally mediated or peripheral\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The demonstration that APLP2's KPI domain inhibits plasma clotting and that APLP2-null mice are prothrombotic established a non-redundant anticoagulant function distinct from APP.\",\n      \"evidence\": \"Recombinant KPI domain clotting assays and carotid artery thrombosis/ICH models in KO mice\",\n      \"pmids\": [\"19403832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific serine protease target(s) of APLP2 KPI domain in coagulation cascade not identified\", \"Contribution of circulating versus membrane-bound APLP2 to hemostasis unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic dissection in APPsα-DM mice (secreted APP ectodomain on APLP2-null background) pinpointed that APP/APLP2 membrane-anchored forms—not secreted ectodomains alone—are essential for neuromuscular transmission and hippocampal LTP, and identified the APP/Mint2/Munc18 complex as the presynaptic mechanism.\",\n      \"evidence\": \"APPsα knock-in × APLP2 KO, neuromuscular and hippocampal electrophysiology, co-IP of APP/Mint2/Munc18\",\n      \"pmids\": [\"21522131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APLP2 independently forms a Mint2/Munc18 complex or only via APP\", \"Structural basis of APP-Mint2 interaction at NMJ not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two discoveries extended APLP2 function beyond neurons: APLP2 mediates pH-dependent lysosomal targeting of PCSK9 (a non-redundant function not shared by APP), and APLP2 inversely regulates MHC class I surface expression in Ewing's sarcoma cells, linking APLP2 to cholesterol metabolism and immune evasion.\",\n      \"evidence\": \"Co-IP with pH-dependent binding and lysosomal trafficking assays for PCSK9; siRNA knockdown with flow cytometry for MHC class I\",\n      \"pmids\": [\"23430252\", \"24353913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether APLP2-mediated PCSK9 degradation affects LDL receptor levels and cholesterol in vivo\", \"Mechanism by which APLP2 retains MHC class I intracellularly not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of APPL2's BAR-domain interaction with TBC1D1 and its inhibitory effect on insulin-stimulated GLUT4 translocation in skeletal muscle, with conditional KO enhancing glucose tolerance, established APLP2 as a metabolic brake on insulin signaling.\",\n      \"evidence\": \"BAR domain mapping, TBC1D1 phosphorylation site analysis, GLUT4 translocation, conditional skeletal muscle KO mice\",\n      \"pmids\": [\"24879834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Note: this discovery concerns APPL2 (adaptor protein), which is a distinct gene from APLP2 (APP-like protein 2); potential gene name confusion should be verified\", \"Whether TBC1D1 interaction is direct or scaffolded\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Multiple studies converged to show that APLP2's intracellular domain binds presynaptic release machinery and enhances NMDA receptor surface expression, while APLP2-null mice display refractive errors (hyperopia) and altered retinal physiology, broadening its synaptic and sensory roles.\",\n      \"evidence\": \"Peptide mapping and hippocampal slice electrophysiology for presynaptic function; co-IP from brain and surface expression assays for NMDAR; refractive measurement and retinal electrophysiology in KO mice\",\n      \"pmids\": [\"26551565\", \"25683482\", \"26313004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether APLP2 directly binds SNARE proteins or acts through Mint adaptors\", \"Mechanism linking APLP2 loss to hyperopia and amacrine cell dysfunction unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that APPL2 promotes glucose-stimulated insulin secretion in beta-cells by sequestering RacGAP1 via its BAR-PH domain to permit Rac1 activation and F-actin remodeling established a cell-type-specific secretory mechanism.\",\n      \"evidence\": \"Beta-cell-specific KO mice, live-cell imaging, Rac1 activation assay, co-IP of APPL2-RacGAP1, RacGAP1 KD rescue\",\n      \"pmids\": [\"33122440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Note: this discovery also concerns APPL2 (adaptor protein) rather than amyloid precursor-like protein 2; gene identity should be verified\", \"Whether APPL2-RacGAP1 interaction is regulated by additional kinases\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Conditional DKO of APP and APLP2 in hippocampal neurons revealed impaired ER Ca²⁺ store refilling through altered SERCA function and Stim1/Stim2 expression, with AAV-mediated APPsα rescue restoring Ca²⁺ homeostasis and LTP, identifying the molecular effectors downstream of APP/APLP2 loss.\",\n      \"evidence\": \"Conditional DKO neurons, Ca²⁺ imaging, SERCA assays, Stim1/Stim2 quantification, AAV-APPsα rescue, LTP recordings\",\n      \"pmids\": [\"34172567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APLP2 alone contributes to SERCA regulation or only in concert with APP\", \"How APPsα restores Stim protein expression mechanistically\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of trans-cellular APLP2-CD11b interaction between GABAergic interneurons and microglia, where nerve injury-induced APLP2 downregulation triggers microglia activation and pain sensitization, established APLP2 as a neuron-glia checkpoint molecule.\",\n      \"evidence\": \"Co-IP of APLP2 with CD11b, GAD2-Cre conditional KD, pain behavioral assays, microglia activation markers\",\n      \"pmids\": [\"36442651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of APLP2-CD11b trans-interaction not defined\", \"Whether this interaction occurs outside spinal cord pain circuits\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies extended APLP2 signaling: the gamma-secretase-generated AICD2 fragment translocates to the nucleus and activates NF-κB via p65 interaction (promoting macrophage antimicrobial function), and APLP2 promotes TGFBR2 degradation by disrupting its Hsp90-mediated stabilization, placing APLP2 in innate immune and TGF-β pathways.\",\n      \"evidence\": \"AICD2 nuclear translocation, co-IP with p65, NF-κB reporter, M. tuberculosis killing assay; co-IP with TGFBR2/Hsp90, ubiquitination assay, TGF-β reporter\",\n      \"pmids\": [\"37844466\", \"37479189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AICD2-p65 interaction awaits structural characterization\", \"Whether APLP2-mediated TGFBR2 degradation occurs in physiological (non-overexpression) settings\", \"Genome-wide transcriptional targets of AICD2-NF-κB not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of APLP2's diverse protein interactions (secretase-generated fragments, KPI domain targets, CD11b trans-binding), whether secreted sAPLP2 acts through a dedicated receptor, and the in vivo significance of APLP2-derived Aβ-like peptides.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of full-length APLP2 or its complexes available\", \"Dedicated receptor for sAPLP2 not identified\", \"Physiological relevance of APLP2 Aβ-like peptides uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 23, 24, 36]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 19, 20, 26]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [14, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 17, 24, 31]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [37]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [13, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 16, 19, 27, 28, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 20, 32, 36, 37]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 11, 38]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [24, 37]}\n    ],\n    \"complexes\": [\n      \"APP/Mint2/Munc18 presynaptic complex\"\n    ],\n    \"partners\": [\n      \"APP\",\n      \"ADAM10\",\n      \"PCSK9\",\n      \"TGFBR2\",\n      \"ITGAM\",\n      \"MINT2\",\n      \"GluN1\",\n      \"BAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"APLP2 is a type I transmembrane glycoprotein of the APP family that functions as a multifunctional regulator of cell adhesion, synaptic transmission, intracellular signaling, and metabolic homeostasis. APLP2 undergoes regulated ectodomain shedding by ADAM10/TACE and sequential intramembranous cleavage by β-secretase (BACE1) and γ-secretase to release a transcriptionally active intracellular domain (ALID2/AICD2) that activates gene expression through complexes with Fe65, Mint3, and co-activators Taz/Yap, as well as through NF-κB p65 [PMID:12228233, PMID:21178287, PMID:37844466]. APLP2 homo- and heterodimerizes with APP and APLP1 to mediate trans-cellular adhesion, and its intracellular domain interacts with presynaptic release machinery, NMDA receptor subunit GluN1, Mint2/Munc18, and the trafficking adaptor PAT1a to regulate neurotransmitter release, synaptic plasticity, and Ca²⁺ homeostasis via SERCA and Stim1/Stim2 [PMID:16193067, PMID:21522131, PMID:25683482, PMID:34172567]. Genetic studies in mice reveal essential, functionally redundant roles with APP in postnatal survival, neuromuscular junction integrity, cortical neurogenesis, glucose/insulin homeostasis, copper homeostasis, refractive eye development, and anticoagulation via its Kunitz protease inhibitor domain [PMID:9461064, PMID:23345401, PMID:18393365, PMID:10526140, PMID:26313004, PMID:19403832].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Molecular cloning established APLP2 as the closest APP homologue, defining its shared domain architecture (signal peptide, KPI domain, transmembrane segment, cytoplasmic NPXY motif) and raising the question of whether the two proteins have overlapping functions.\",\n      \"evidence\": \"cDNA cloning and sequence/domain analysis from two independent groups\",\n      \"pmids\": [\"8220435\", \"8485127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data; domain homology does not prove functional equivalence\", \"Predicted G(o)-coupling lacked biochemical validation\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of Ser-614 as the sole chondroitin sulfate GAG modification site, and the subsequent demonstration that alternative splicing controls GAG addition, revealed an isoform-specific post-translational modification with potential implications for axonal targeting.\",\n      \"evidence\": \"Site-directed mutagenesis in CHO/COS-1 cells with chondroitinase digestion; isoform-specific expression analysis\",\n      \"pmids\": [\"8071334\", \"7622456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CS-GAG modification on APLP2 biology remained undefined\", \"Mechanism by which the 12-aa insertion blocks GAG addition was not determined structurally\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"The demonstration that APP/APLP2 double knockout mice die postnatally while single knockouts are viable established functional redundancy between the two genes and motivated all subsequent compound genetic analyses.\",\n      \"evidence\": \"Gene targeting and double-KO mouse generation with postnatal lethality phenotype\",\n      \"pmids\": [\"9461064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of postnatal lethality was undefined\", \"Whether APLP1 could also compensate remained to be tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Loss-of-function studies in knockout mice revealed APLP2's role in copper homeostasis and its neurotrophic properties, broadening the functional repertoire beyond structural homology with APP.\",\n      \"evidence\": \"Atomic absorption spectrophotometry in APLP2-KO mouse tissues; recombinant sAPLP2 neurite outgrowth assay in chick sympathetic neurons\",\n      \"pmids\": [\"10526140\", \"9923612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Copper-binding site on APLP2 not mapped\", \"Receptor mediating sAPLP2 neurotrophic activity unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that BACE1 and γ-secretase sequentially cleave APLP2 to release a transcriptionally active intracellular domain (ALID2) that activates Fe65-dependent gene expression established APLP2 as a signaling molecule processed analogously to Notch.\",\n      \"evidence\": \"BACE1 overexpression cleavage assays combined with transcriptional reporter assays; Presenilin 1-dependent γ-secretase cleavage demonstration\",\n      \"pmids\": [\"12228233\", \"14699153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes of ALID2/Fe65 were not identified\", \"Physiological relevance of ALID2 signaling in vivo not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of ADAM10 and TACE as the α-secretases mediating APLP2 ectodomain shedding, combined with the discovery that APP/APLP2 homo- and heterodimerize to mediate trans-cellular adhesion, integrated APLP2 into both regulated proteolysis and cell adhesion pathways.\",\n      \"evidence\": \"ADAM10/TACE overexpression and inhibitor studies in cells plus ADAM10-transgenic mice; Co-IP from mouse brain and KO MEF adhesion assays with rescue\",\n      \"pmids\": [\"16279945\", \"16193067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of homo/heterodimerization interface not resolved\", \"Relative contributions of cis vs. trans dimerization to adhesion in vivo unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The KPI domain of APLP2 was shown to inhibit coagulation proteases with anticoagulant effects in vivo, and the trafficking adaptor PAT1a was identified as a regulator of APLP2 surface levels and processing, establishing two distinct functional axes—hemostasis and intracellular trafficking.\",\n      \"evidence\": \"Recombinant KPI domain clotting assays and APLP2-KO thrombosis models; PAT1a Co-IP, RNAi, and surface biotinylation in primary neurons\",\n      \"pmids\": [\"19403832\", \"17050537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo bleeding/clotting phenotype in humans not assessed\", \"PAT1a binding stoichiometry and competition with Fe65 not determined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"APP/APLP2 double knockouts revealed essential roles in glucose/insulin homeostasis and glutamatergic neurotransmission (via VGLUT2 regulation by the intracellular domain), connecting APLP2 to metabolic and synaptic functions.\",\n      \"evidence\": \"Double-KO metabolic phenotyping; ESC-derived neurons from double-KO with γ-secretase inhibition and APP-ICD rescue, VGLUT2 quantification, electrophysiology\",\n      \"pmids\": [\"18393365\", \"18535156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APLP2 alone is sufficient for glucose homeostasis not separated from APP contribution\", \"Mechanism linking intracellular domain to VGLUT2 transcription not fully defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Electrophysiological studies in compound mutant mice established that APP and APLP2 are synergistically required for neuromuscular transmission and hippocampal LTP, with the underlying mechanism involving an APP/Mint2/Munc18 presynaptic complex and Mint3-Taz/Yap transcriptional complexes.\",\n      \"evidence\": \"APPsα-KI × APLP2-KO mice with NMJ and hippocampal electrophysiology, Co-IP of APP/Mint2/Munc18; Co-IP and reporter assays for Mint3-Taz/Yap complexes\",\n      \"pmids\": [\"21522131\", \"21178287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes of Mint3-Taz/Yap complexes downstream of APLP2 not identified\", \"Whether APLP2 directly recruits Mint2/Munc18 or acts indirectly through APP not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"APLP2 was shown to have unique functions not shared with APP: it mediates PCSK9-dependent LDLR lysosomal degradation and is specifically required for cortical progenitor cell cycle exit during neurogenesis, although the PCSK9 requirement was later challenged.\",\n      \"evidence\": \"APLP2 KD/KO with LDLR readout and pH-dependent binding assays; in vivo shRNA in APP/APLP1-DKO background with mitotic index quantification; PCSK9 infusion in multiple KO lines contradicting APLP2 requirement\",\n      \"pmids\": [\"23430252\", \"23345401\", \"28495363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PCSK9/APLP2 interaction is contested—in vivo infusion studies found APLP2 dispensable for PCSK9 function\", \"Neurogenesis mechanism downstream of APLP2 (transcriptional targets, signaling pathway) not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Multiple studies converged on synaptic and sensory functions: APLP2's intracellular domain interacts with presynaptic release machinery to regulate glutamate release; APLP2 associates with NMDA receptors via GluN1 to enhance their surface expression; and Aplp2 knockout mice develop hyperopia with altered retinal amacrine cell function.\",\n      \"evidence\": \"Domain mapping and JCasp peptide interference with hippocampal slice electrophysiology; Co-IP of APLP2/GluN1 from brain; Aplp2-KO refraction, ERG, and retinal immunostaining\",\n      \"pmids\": [\"26551565\", \"25683482\", \"26313004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of APLP2-GluN1 interaction not resolved\", \"Molecular pathway linking APLP2 to amacrine cell physiology and emmetropization unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The mechanism by which APP/APLP2 control synaptic plasticity was traced to Ca²⁺ homeostasis: double knockout disrupts ER Ca²⁺ store refilling via altered SERCA function and Stim1/Stim2 expression, and this is rescued by secreted APPsα, linking ectodomain shedding to ER calcium signaling.\",\n      \"evidence\": \"Conditional double-KO hippocampal neurons with Ca²⁺ imaging, SERCA assays, Stim1/2 quantification, AAV-APPsα rescue, and LTP electrophysiology\",\n      \"pmids\": [\"34172567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APLP2-derived soluble ectodomain alone can rescue Ca²⁺ defects not tested\", \"Identity of the receptor mediating APPsα's effect on SERCA/Stim expression unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The transcriptional output of the APLP2 intracellular domain was extended to NF-κB signaling: nuclear AICD2 interacts with NF-κB p65 to upregulate IL-1β and iNOS in macrophages, and this antimicrobial pathway is exploited during mycobacterial defense; simultaneously, APLP2 was shown to inhibit TGF-β signaling by disrupting TGFBR2-Hsp90 stabilization.\",\n      \"evidence\": \"Co-IP of nuclear AICD2/p65, NF-κB reporter, KO mouse infection model; Co-IP of APLP2/TGFBR2/Hsp90 with ubiquitination and signaling readouts\",\n      \"pmids\": [\"37844466\", \"37479189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-κB target gene repertoire regulated by AICD2 not comprehensively defined\", \"TGF-β pathway modulation studied only in overexpression systems\", \"Neither finding independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of APLP2 dimerization interfaces, the full transcriptional target repertoire of ALID2/AICD2 in vivo, whether the contested PCSK9-APLP2 axis is physiologically relevant, and the receptor(s) mediating sAPLP2 neurotrophic and Ca²⁺-regulatory signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of full-length APLP2 or its dimerization interface\", \"ChIP-seq or equivalent genome-wide identification of AICD2 targets not performed\", \"Receptor for soluble APLP2 ectodomain signaling remains unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [16, 20, 34]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10, 11, 25, 39]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [19, 40]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [18, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 16, 23, 46]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [25, 39]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [18, 23]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [8, 15, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [22, 24, 30, 32, 36, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 25, 39, 40, 42]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [16, 20, 38]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3, 10, 11, 12, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [27, 31]}\n    ],\n    \"complexes\": [\n      \"APP family homo/heterodimer complex\",\n      \"ALID2/Fe65 transcriptional complex\",\n      \"Mint3-Taz/Yap transcriptional complex\",\n      \"APP/Mint2/Munc18 presynaptic complex\"\n    ],\n    \"partners\": [\n      \"APP\",\n      \"APLP1\",\n      \"FE65\",\n      \"MINT3\",\n      \"ADAM10\",\n      \"BACE1\",\n      \"PCSK9\",\n      \"GLUN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}