{"gene":"APLP2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1993,"finding":"APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o), suggesting it may function as a cell surface activator of this G protein, similar to APP.","method":"Sequence analysis and structural prediction of cloned APLP2 gene","journal":"Nature genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/structural prediction only, no direct binding experiment performed","pmids":["8220435"],"is_preprint":false},{"year":1994,"finding":"APLP2 is modified by chondroitin sulfate (CS) glycosaminoglycan addition at a single site (Ser-614); a serine-to-alanine substitution at position 614 abolishes CS GAG modification, identifying this as the sole modification site.","method":"Stable transfection of CHO and COS-1 cells, chondroitinase AC digestion, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro mutagenesis with direct biochemical readout, clearly defined mechanism","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 N-terminal to Ser-614, is not modified by CS GAG, whereas APLP2-751 is. Similarly, APP isoforms lacking exon 15 sequences (L-APP) are CS GAG-modified, whereas those containing exon 15 are not.","method":"Expression of alternatively spliced isoforms in transfected cells, chondroitinase digestion, biochemical analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct mutagenesis/isoform expression with biochemical validation, single lab but multiple orthogonal approaches","pmids":["7622456"],"is_preprint":false},{"year":1995,"finding":"APLP2 is enriched in postsynaptic compartments in cortex and hippocampus, and is abundant in olfactory sensory axons and axon terminals in glomeruli; CS GAG-modified APLP2 forms are enriched in olfactory epithelium and accumulate in the olfactory bulb, consistent with a role in axonal pathfinding and/or synaptogenesis.","method":"Immunocytochemistry with APLP2-specific antibodies, confocal microscopy, biochemical fractionation","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunocytochemistry and confocal microscopy, functional implication inferred but not directly tested","pmids":["7472397"],"is_preprint":false},{"year":1997,"finding":"APLP2 and APP are functionally redundant in vivo: APLP2 single KO mice are viable and fertile, but APP/APLP2 double KO mice exhibit ~80% early postnatal lethality, demonstrating that APLP2 and APP can substitute for each other functionally.","method":"Generation of APLP2 KO and APP/APLP2 double KO mice, phenotypic analysis","journal":"Neurobiology of aging","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double knockout with clear phenotypic readout, widely replicated","pmids":["9461064"],"is_preprint":false},{"year":1998,"finding":"APLP2 is required for correct genomic segregation in dividing cells: homozygous APLP2 deletion embryos arrest before the blastocyst stage with abnormal nuclear DNA content (departing from normal 2-4C values), and antisense suppression in fibroblasts produces daughter cells with abnormal DNA contents, indicating a role in mitotic genome segregation.","method":"Generation of large genomic deletion in mice, DNA content analysis, antisense RNA transfection in fibroblasts","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype (DNA content abnormality), two approaches (KO embryos + antisense), single lab","pmids":["9707424"],"is_preprint":false},{"year":1999,"finding":"APP and APLP2 expression specifically modulates copper homeostasis in the liver and cerebral cortex; APP(-/-) and APLP2(-/-) mice show significantly elevated copper levels in cerebral cortex (40% and 16%, respectively) and liver (80% and 36%, respectively) compared to wild-type, with no significant differences in zinc or iron.","method":"Atomic absorption spectrophotometry of tissue from APP(-/-) and APLP2(-/-) knockout mice","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct measurement in KO mice with specificity for copper vs other metals, single lab","pmids":["10526140"],"is_preprint":false},{"year":1999,"finding":"Recombinant soluble APLP2 ectodomain (sAPLP2) promotes neurite outgrowth in chick sympathetic neurons with activity similar to APP isoforms sAPP695 and sAPP751.","method":"Expression of recombinant sAPLP2 in Pichia pastoris, neurite outgrowth assay on chick sympathetic neurons","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with purified recombinant protein, single lab","pmids":["9923612"],"is_preprint":false},{"year":2001,"finding":"APLP2 ectodomain shedding in corneal epithelial cells is regulated by MAP kinase (MAPK): basal shedding and that induced by PKC activator PMA or EGF is blocked by the MEK inhibitor U-0126; PKC-epsilon is involved in PMA- and EGF-induced shedding.","method":"Western blotting, flow cytometry, indirect immunofluorescence, pharmacological inhibition with U-0126 and PKC-epsilon inhibitor in human corneal epithelial cells","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with multiple inhibitors and multiple readout methods, single lab","pmids":["11443060"],"is_preprint":false},{"year":2004,"finding":"APLP2 is processed by alpha-, beta-, gamma-, and epsilon-secretase-like cleavages, producing C-terminal fragments, intracellular domains (AICD-like), and p3-like and Abeta-like fragments. BACE (beta-secretase) modulates APLP2 processing in vivo: APLP2 proteolytic products are decreased in BACE KO mice and increased in BACE transgenic mice; overexpression of BACE in cultured cells increases APLP2 processing.","method":"C-terminally tagged constructs in stably transfected SH-SY5Y cells, pharmacological inhibitors, BACE KO and transgenic mice, Western blot","journal":"The Journal of biological chemistry; Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple pharmacological inhibitors, KO and transgenic animal models, replicated across two independent studies","pmids":["14970212","15080893"],"is_preprint":false},{"year":2005,"finding":"APLP2 is a substrate for the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17): overexpression of either proteinase in HEK293 cells increases shedding of soluble APLP2 severalfold; ADAM10-preferring inhibitor most strongly reduces shedding in neuroblastoma cells; ADAM10 transgenic mice show significantly increased soluble APLP2 and its C-terminal fragments.","method":"Overexpression of ADAM10/TACE in HEK293 cells, pharmacological inhibition in neuroblastoma cells, ADAM10 transgenic mice, Western blot","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — gain-of-function overexpression, pharmacological inhibition, and in vivo transgenic validation, multiple methods","pmids":["16279945"],"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 APP and both Cu(II) and Cu(I) forms of APLP2 inhibit glypican-1 autodegradation; in primary cortical neurons from APP or APLP2 KO mice, nitric oxide-catalyzed heparan sulfate degradation is increased; in APLP2 KO (but not APP KO) fibroblasts, heparan sulfate degradation is also increased.","method":"Cell-free biochemical experiments, confocal immunofluorescence microscopy, flow cytometry, primary neurons and fibroblasts from KO mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (cell-free, imaging, KO cells), clear mechanistic distinction between APP and APLP2 roles","pmids":["15677459"],"is_preprint":false},{"year":2006,"finding":"PAT1a binds directly to APP, APLP1, and APLP2 in vivo and co-localizes with them in trans-Golgi network vesicles or endosomes in primary neurons; PAT1a interacts with the basolateral sorting signal of APP/APLPs; overexpression or RNAi knockdown of PAT1a modulates APP/APLP surface levels and promotes their processing, resulting in increased Abeta secretion.","method":"Co-immunoprecipitation, co-localization in primary neurons, overexpression and RNAi knockdown, cell surface assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, co-localization, gain- and loss-of-function with functional readouts, single lab but multiple orthogonal approaches","pmids":["17050537"],"is_preprint":false},{"year":2006,"finding":"APP and APLP2 are required for keratinocyte proliferation, migration, and adhesion: keratinocytes from APP/APLP2 double KO mice show ~40% reduced proliferation in vivo and in vitro, reduced migration velocity, and compromised cell-substrate adhesion; double KO keratinocytes die within the first week of culture. Proliferation deficits are rescued by exogenous recombinant sAPPalpha.","method":"KO mouse keratinocyte isolation, proliferation assays, migration assays, rescue with recombinant sAPPalpha","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined phenotypic readouts and rescue experiment, single lab","pmids":["16584729"],"is_preprint":false},{"year":2008,"finding":"APP and APLP2 are required for normal glucose and insulin homeostasis: APP/APLP2 double KO mice show 66% lower plasma glucose and hyperinsulinemia compared to wild-type at postnatal day, identifying a role for APP/APLP2 in modulating plasma insulin and glucose concentrations.","method":"Plasma analysis from double KO mice at E17 and postnatal, glucose and insulin measurements","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical measurement in KO mice with specific metabolic readout, single lab","pmids":["18393365"],"is_preprint":false},{"year":2008,"finding":"Loss of APP and APLP2 in neurons leads to decreased expression of vesicular glutamate transporter 2 (VGLUT2) and reduced glutamate uptake/release; blocking gamma-secretase in wild-type neurons similarly decreases VGLUT2; VGLUT2 levels can be restored in double KO neurons by a construct encoding the C-terminal intracellular domain of APP, indicating the intracellular domain mediates this function.","method":"ESC-derived neurons from APP/APLP2 double KO mice, VGLUT2 mRNA and protein quantification, gamma-secretase inhibition, APP intracellular domain rescue construct, electrophysiology in hippocampal slices","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (KO neurons, pharmacological inhibition, rescue construct, electrophysiology), mechanistic pathway defined","pmids":["18535156"],"is_preprint":false},{"year":2009,"finding":"APLP2 and APP share overlapping anticoagulant functions: recombinant KPI domains of both proteins inhibit plasma clotting in vitro; APLP2(-/-) and APP(-/-) mice both exhibit significantly shorter times to carotid artery occlusion and produce smaller hematomas in intracerebral hemorrhage models, indicating a prothrombotic phenotype when APLP2 is absent.","method":"Recombinant KPI domain inhibition assays, carotid artery thrombosis model, intracerebral hemorrhage model in KO mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemical assay plus two in vivo KO models with defined functional readouts","pmids":["19403832"],"is_preprint":false},{"year":2009,"finding":"Live cell imaging shows that APLP2 localizes predominantly to intracellular compartments (unlike APLP1 which is mainly at the cell surface); APLP2 forms homo- and heterotypic cis interactions with APP family members detectable by FRET and co-immunoprecipitation; interactions occur in a modular mode with the N-terminal half of the ectodomain crucial for APP-APLP2 interactions; coexpression of APP with APLP2 leads to diminished Abeta42 generation, attributed to heteromeric complex formation.","method":"Live cell imaging, FRET, co-immunoprecipitation, deletion mutant analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (live imaging, FRET, Co-IP, deletion mutants) with functional readout (Abeta42 generation)","pmids":["19126676"],"is_preprint":false},{"year":2011,"finding":"APLP2 and APP are synergistically required for neuromuscular transmission: APPsα-DM mice (expressing only secreted APPsα on APLP2-null background) show impaired neuromuscular transmission with reductions in quantal content, readily releasable pool, and vesicle release sustainability, resulting in muscular weakness; defects are associated with loss of an APP/Mint2/Munc18 complex; APPsα-DM muscle shows fragmented postsynaptic specializations.","method":"APPsα knock-in mice crossed onto APLP2-deficient background, electrophysiology, co-immunoprecipitation of APP/Mint2/Munc18 complex, morphological analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic rescue experiment with defined physiological readout, Co-IP of complex, morphological and electrophysiological validation","pmids":["21522131"],"is_preprint":false},{"year":2011,"finding":"APLP2 mediates signaling via formation of transcriptionally active triple protein complexes with adaptor protein Mint3 and transcriptional co-activators Taz and Yap; complex formation is regulated by gamma-secretase cleavage of APLP2; Mint1 (instead of Mint3) prevents nuclear translocation of the complex.","method":"Co-immunoprecipitation, transactivation assays, gamma-secretase inhibition","journal":"Journal of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and functional transactivation assays, single lab, multiple complex members identified","pmids":["21178287"],"is_preprint":false},{"year":2013,"finding":"APLP2 is required for proper cell cycle exit of cortical neuronal progenitors: silencing APLP2 in vivo in an APP/APLP1 double KO background causes cortical progenitors to remain undifferentiated longer with a higher number of mitotic cells; neuron-specific APLP2 downregulation does not affect the speed or position of migrating excitatory cortical neurons.","method":"shRNA-mediated APLP2 silencing in vivo in APP/APLP1 double KO mice, analysis of mitotic cells and neuronal differentiation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with specific cellular phenotype, defined genetic background, single lab","pmids":["23345401"],"is_preprint":false},{"year":2013,"finding":"PCSK9 interacts directly with APLP2 (but not APP) via its C-terminal domain in a pH-dependent manner; APLP2 (but not APP) mediates postendocytic delivery of PCSK9 to lysosomes, making it required for PCSK9 function in LDLR degradation.","method":"Co-immunoprecipitation, pH-dependent binding assays, cell-based PCSK9 trafficking assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with functional readout (lysosomal delivery), single lab, direct binding demonstrated","pmids":["23430252"],"is_preprint":false},{"year":2013,"finding":"APLP2 co-immunoprecipitates with MHC class I molecules in Ewing's sarcoma cells; irradiation redistributes APLP2 and MHC class I on the cell surface; APLP2 siRNA knockdown increases MHC class I surface expression, indicating APLP2 inhibits MHC class I surface expression.","method":"Co-immunoprecipitation, flow cytometry, siRNA knockdown","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and loss-of-function with defined functional readout, single lab","pmids":["24353913"],"is_preprint":false},{"year":2014,"finding":"APP/APLP2 expression is required for transport of anhydromannose-containing heparan sulfate from endosomes to the nucleus and subsequently to autophagosomes: nuclear HS translocation is seen in WT but not APP(-/-) or APLP2(-/-) MEFs; transfection of APP restores nuclear import; beta- and gamma-secretase inhibitors block nuclear transport, implicating APP/APLP2 degradation products.","method":"Deconvolution immunofluorescence microscopy with anMan-specific antibody, 35S-labeling, secretase inhibitor treatment, APP(-/-) and APLP2(-/-) MEFs, transfection rescue","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (imaging, labeling, KO, rescue), single lab","pmids":["24898256"],"is_preprint":false},{"year":2015,"finding":"APP and APLP2 interact with the synaptic release machinery via the NH2-terminal region of their intracellular domains; a peptide (JCasp) naturally produced by gamma-secretase/caspase double-cut of APP interferes with APP-presynaptic protein interactions and reduces glutamate release in hippocampal slices from wild-type but not APP-deficient mice; deletion of APP and APLP2 produces synaptic deficits similar to those caused by JCasp.","method":"Mapping of binding domain, JCasp cell-penetrating peptide treatment, glutamate release assay in acute hippocampal slices, APP/APLP2 double KO comparison","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mapping, specific peptide interference, multiple genetic controls (KO vs WT), clear functional readout","pmids":["26551565"],"is_preprint":false},{"year":2015,"finding":"APLP2 co-immunoprecipitates with NMDA receptor subunits GluN1/GluN2A and GluN1/GluN2B in mammalian cells and in adult brain; interaction is via GluN1 subunit; APLP2 enhances GluN1/GluN2A and GluN1/GluN2B cell surface expression.","method":"Co-immunoprecipitation from transfected cells and adult brain lysates, cell surface expression assays","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP in cells and native brain tissue, functional surface expression assay, single lab","pmids":["25683482"],"is_preprint":false},{"year":2015,"finding":"APLP2 knockdown in pancreatic cancer cells reduces migration and invasion, decreases cortical actin, and increases intracellular actin filaments; APLP2 knockdown reduces tumor weight and metastasis in orthotopic mouse models, indicating APLP2 affects actin cytoskeleton organization to promote cancer cell migration.","method":"Inducible shRNA knockdown, migration/invasion assays, actin cytoskeleton imaging, orthotopic tumor transplantation in mice","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular and in vivo phenotypes, single lab","pmids":["25576918"],"is_preprint":false},{"year":2015,"finding":"Aplp2 knockout mice develop high degrees of hyperopia and exhibit dose-dependent reduction in susceptibility to environmentally induced myopia; the 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, contrast sensitivity testing, retinal electrophysiology","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotyping with multiple functional readouts, single lab","pmids":["26313004"],"is_preprint":false},{"year":2017,"finding":"APP, APLP2, and LRP1 all interact with PCSK9, but none is required for PCSK9-mediated LDLR degradation in vivo: infusion of PCSK9 into App(-/-), Aplp2(-/-), Aplp2-depleted App(-/-), or liver-specific Lrp1(-/-) mice results in similar reductions in hepatic LDLR as in wild-type mice.","method":"Co-immunoprecipitation, PCSK9 infusion into multiple KO mouse lines, hepatic LDLR measurement","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with direct functional readout, negative result for APLP2 requirement in LDLR degradation is mechanistically informative; contradicts PMID 23430252 partial conclusion","pmids":["28495363"],"is_preprint":false},{"year":2018,"finding":"APLP2 promotes cell migration in Drosophila via JNK signaling: ectopic APLP2 expression activates JNK by phosphorylation, which triggers MMP1 expression required for basement membrane degradation and cell migration; loss of JNK suppresses APLP2-induced migration while gain of JNK enhances it.","method":"Drosophila ectopic expression, JNK loss- and gain-of-function epistasis, phosphorylation assays, MMP1 expression analysis","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Drosophila model organism with defined pathway, consistent with mammalian context but in Drosophila","pmids":["30155482"],"is_preprint":false},{"year":2020,"finding":"Loss of APP and APLP2 specifically in GABAergic forebrain neurons (DlxCre cDKO) impairs synaptic plasticity (LTP), spatial learning, and excitation/inhibition balance; reduced action potential firing of CA1 pyramidal cells and altered excitatory/inhibitory synaptic currents indicate APP family proteins in inhibitory interneurons maintain functional network activity.","method":"Conditional double KO using DlxCre, electrophysiology (LTP, synaptic currents), behavioral testing, morphological analysis","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with multiple orthogonal readouts (electrophysiology, behavior, morphology), single lab but rigorous","pmids":["32219307"],"is_preprint":false},{"year":2021,"finding":"APP and APLP2 together control neuronal Ca2+ homeostasis; loss of both (but not APLP2 alone) impairs Ca2+ handling, ER Ca2+ store refill, and synaptic plasticity via altered SERCA-ATPase function and expression of store-operated Ca2+ channel-associated proteins Stim1 and Stim2; long-term AAV-mediated expression of APPsα (but not acute application) restores Ca2+ homeostasis and LTP in APP/APLP2 cDKO neurons.","method":"APP/APLP2 conditional double KO neurons, Ca2+ imaging, SERCA-ATPase and Stim1/Stim2 expression analysis, AAV-mediated APPsα rescue, LTP recordings","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO with specific molecular mechanism (SERCA, Stim1/2), genetic rescue experiment, multiple orthogonal methods","pmids":["34172567"],"is_preprint":false},{"year":2022,"finding":"Peripheral nerve injury reduces APLP2 expression specifically in spinal GABAergic inhibitory interneurons; targeted knockdown of APLP2 in GAD2-positive neurons evokes pain hypersensitivity via microglial activation; APLP2 at GABAergic terminals interacts with microglia-specific integrin CD11b in a trans-cellular manner, and disruption of this interaction leads to microglia-dependent pain sensitization.","method":"Nerve injury model, conditional APLP2 knockdown in GAD2-Cre mice, co-immunoprecipitation of APLP2 with CD11b, pain behavioral testing, microglial activation assays","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — cell-type-specific KD with defined phenotype and Co-IP of binding partner, single lab","pmids":["36442651"],"is_preprint":false},{"year":2023,"finding":"APLP2 (as YWK-II/APLP2) inhibits TGF-β signaling by promoting degradation of TGFBR2: APLP2 associates with TGFBR2 in a TGF-β activity-dependent manner, binds Hsp90 to interfere with the TGFBR2-Hsp90 stabilizing interaction, and leads to enhanced ubiquitination and degradation of TGFBR2; knockdown of APLP2 increases TGFBR2 protein level and sensitizes cells to TGF-β, while overexpression destabilizes TGFBR2.","method":"Co-immunoprecipitation, knockdown and overexpression experiments, ubiquitination assays, TGF-β signaling readouts","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with Hsp90 and TGFBR2, gain/loss-of-function with functional readout, mechanistic model supported by multiple assays, single lab","pmids":["37479189"],"is_preprint":false},{"year":2023,"finding":"The APLP2 cleaved intracellular domain product (AICD2), generated by gamma-secretase, translocates to the nucleus where it interacts with p65, enhancing NF-κB transcriptional activity to upregulate IL-1β and iNOS expression; APLP2 mutation/knockdown reduces macrophage-mediated killing of Mycobacterium tuberculosis.","method":"Aplp2 mutant/knockdown macrophages, nuclear translocation assay, co-immunoprecipitation with p65, NF-κB reporter assays, iNOS and IL-1β measurement, M.tb infection in KO mice","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of AICD2 with p65, multiple loss-of-function approaches and in vivo KO, single lab","pmids":["37844466"],"is_preprint":false},{"year":2012,"finding":"Bat3 interacts with APLP2 (YWK-II/APLP2) and enhances its stability by reducing ubiquitylation and proteasomal degradation; the proline-rich domain of Bat3 is required for binding to APLP2; nuclear export of Bat3 under apoptotic stimulation elevates APLP2 protein levels.","method":"Co-immunoprecipitation, domain deletion analysis, ubiquitylation assays, apoptosis stimulation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with domain mapping, ubiquitylation assay, single lab","pmids":["22641691"],"is_preprint":false},{"year":2026,"finding":"Endothelial APLP2 is required for postischemia angiogenesis after myocardial infarction; hypoxia induces alpha-secretase-mediated processing of APLP2 into soluble APLP2sα; APPsα and APLP2sα exert proangiogenic effects by positive allosteric modulation of the endothelial receptor tyrosine kinase KIT, promoting neovascularization.","method":"Endothelial-specific APP/APLP2 knockout mice, myocardial infarction model, secretase activity assays, KIT receptor signaling assays, AAV rescue with APPsα","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with in vivo functional readout, defined molecular mechanism (KIT allosteric modulation), genetic rescue, single lab","pmids":["42172320"],"is_preprint":false}],"current_model":"APLP2 is a type I transmembrane glycoprotein and APP paralog that is processed by alpha-, beta-, gamma-, and epsilon-secretases (with BACE/beta-secretase predominating in the CNS) and by ADAM10/TACE metalloproteases to release a neurotrophic soluble ectodomain (APLP2sα) and an intracellular domain (AICD2); APLP2 and APP are functionally redundant during postnatal development (double KO mice die perinatally), and together mediate neuromuscular and hippocampal synaptic transmission, spatial learning, and LTP through interactions with the synaptic release machinery (Mint2/Munc18 complex) and NMDA receptors; APLP2 modulates copper homeostasis, acts as a Kunitz-type serine protease inhibitor to regulate cerebral thrombosis, controls neuronal Ca²⁺ homeostasis via SERCA-ATPase and Stim1/2, regulates glypican-1 heparan sulfate catabolism, and its AICD2 fragment activates NF-κB signaling via p65; APLP2 is subject to post-translational regulation including CS glycosaminoglycan modification at Ser-614 (regulated by alternative splicing), ubiquitin-proteasome degradation stabilized by Bat3, and ectodomain shedding regulated by MAPK/PKC signaling; outside the nervous system, APLP2 promotes pancreatic cancer cell migration by reorganizing the actin cytoskeleton, inhibits TGF-β signaling by destabilizing TGFBR2 via competition with Hsp90, modulates MHC class I surface expression, maintains GABAergic interneuron-microglia interactions at the synapse, and endothelial APLP2sα drives postischemic angiogenesis through allosteric activation of the KIT receptor tyrosine kinase."},"narrative":{"mechanistic_narrative":"APLP2 is a type I transmembrane glycoprotein of the APP family that functions in synaptic transmission, neural development, and diverse cell-surface signaling processes, acting largely redundantly with APP [PMID:9461064]. Like APP, APLP2 undergoes sequential proteolytic processing by alpha- and beta-secretases—with BACE modulating its cleavage in vivo [PMID:14970212, PMID:15080893]—and by the metalloproteinases ADAM10 and TACE to shed a soluble neurotrophic ectodomain [PMID:16279945, PMID:9923612], followed by gamma-/epsilon-secretase cleavage that liberates an intracellular domain (AICD2) [PMID:14970212, PMID:15080893]; ectodomain shedding is controlled by MAPK/PKC-epsilon signaling [PMID:11443060]. APLP2 and APP are functionally redundant during postnatal development, with double knockout causing early lethality [PMID:9461064], and together they sustain neuromuscular and central synaptic transmission: they bind the presynaptic release machinery via the N-terminus of their intracellular domains in a complex with Mint2/Munc18 to support quantal glutamate release [PMID:21522131, PMID:26551565], interact with NMDA receptor GluN1 to promote receptor surface expression [PMID:25683482], control VGLUT2 expression through the intracellular domain [PMID:18535156], and maintain neuronal Ca2+ homeostasis through SERCA-ATPase and Stim1/2 [PMID:34172567]. APP family loss in GABAergic interneurons impairs LTP, spatial learning, and excitation/inhibition balance [PMID:32219307], and APLP2 at GABAergic terminals engages microglial CD11b in trans to restrain pain sensitization [PMID:36442651]. APLP2 forms homo- and heterotypic cis complexes with APP, reducing Abeta42 generation [PMID:19126676], and is subject to post-translational regulation including chondroitin-sulfate modification at Ser-614 governed by alternative splicing [PMID:8071334, PMID:7622456] and Bat3-mediated stabilization against proteasomal degradation [PMID:22641691]. APLP2 also modulates copper homeostasis [PMID:10526140], inhibits plasma clotting through its Kunitz-type protease inhibitor domain [PMID:19403832], and regulates glypican-1 heparan sulfate catabolism [PMID:15677459]. Outside the nervous system, APLP2 promotes pancreatic cancer cell migration via actin reorganization [PMID:25576918], inhibits TGF-beta signaling by destabilizing TGFBR2 through competition with Hsp90 [PMID:37479189], suppresses MHC class I surface expression [PMID:24353913], and its AICD2 fragment activates NF-kB via p65 to drive antimicrobial macrophage responses [PMID:37844466]; endothelial APLP2sα promotes postischemic angiogenesis through allosteric activation of the KIT receptor [PMID:42172320].","teleology":[{"year":1994,"claim":"Established the first defined post-translational modification of APLP2, pinpointing a single chondroitin-sulfate attachment site that would distinguish APLP2 proteoglycan forms.","evidence":"Site-directed mutagenesis (Ser614Ala) and chondroitinase digestion in transfected CHO/COS cells","pmids":["8071334"],"confidence":"High","gaps":["Functional consequence of CS-GAG modification not addressed","Does not connect modification to a downstream signaling or trafficking event"]},{"year":1995,"claim":"Showed that CS-GAG modification of APLP2 is switched by alternative splicing, defining a regulated mechanism for generating proteoglycan versus non-proteoglycan APLP2 isoforms.","evidence":"Isoform expression and chondroitinase analysis of APLP2-751 vs APLP2-763 in transfected cells","pmids":["7622456"],"confidence":"High","gaps":["Physiological role of each isoform unresolved","Tissue-specific splicing regulation not mapped"]},{"year":1997,"claim":"Resolved whether APLP2 has an essential individual function by revealing functional redundancy with APP, a foundational genetic insight for the family.","evidence":"APLP2 single KO and APP/APLP2 double KO mouse phenotyping","pmids":["9461064"],"confidence":"High","gaps":["Molecular basis of redundancy not defined","Specific lethal process in double KO not identified"]},{"year":1999,"claim":"Connected APLP2 to metal handling and to neurotrophic ectodomain activity, broadening its role beyond development.","evidence":"Tissue copper measurement in KO mice and neurite outgrowth assay with recombinant sAPLP2","pmids":["10526140","9923612"],"confidence":"Medium","gaps":["Direct copper-binding mechanism of APLP2 not shown","Receptor mediating sAPLP2 neurite outgrowth unknown"]},{"year":2005,"claim":"Defined the proteolytic machinery acting on APLP2, establishing that it is processed analogously to APP by BACE, ADAM10/TACE, and gamma/epsilon-secretases.","evidence":"Tagged constructs in neuroblastoma cells, secretase overexpression, pharmacological inhibition, and BACE/ADAM10 KO and transgenic mice","pmids":["14970212","15080893","16279945"],"confidence":"High","gaps":["Physiological signaling output of each fragment not fully resolved","Regulation of cleavage site choice in vivo not detailed"]},{"year":2005,"claim":"Distinguished APP from APLP2 in heparan sulfate metabolism, showing APLP2 regulates copper/NO-catalyzed glypican-1 autodegradation.","evidence":"Cell-free copper-form assays, imaging, and KO neurons and fibroblasts","pmids":["15677459"],"confidence":"High","gaps":["In vivo relevance of glypican-1 regulation unclear","Link between this activity and synaptic/developmental roles not made"]},{"year":2009,"claim":"Demonstrated APLP2 forms cis homo- and heteromeric complexes with APP and exerts anticoagulant activity, two distinct mechanistic roles for the protein.","evidence":"FRET, Co-IP, deletion mutants for complex formation; recombinant KPI assays and thrombosis/hemorrhage KO models for anticoagulation","pmids":["19126676","19403832"],"confidence":"High","gaps":["Stoichiometry and physiological abundance of heteromers unknown","Protease target of the KPI domain in vivo not identified"]},{"year":2011,"claim":"Identified the synaptic mechanism by which APLP2/APP support neurotransmission, linking the intracellular domain to the Mint2/Munc18 release machinery.","evidence":"APPsalpha knock-in on APLP2-null background, electrophysiology, Co-IP of APP/Mint2/Munc18 complex","pmids":["21522131"],"confidence":"High","gaps":["Whether APLP2 intracellular domain binds the complex identically to APP not separated","Direct versus adaptor-mediated binding not dissected"]},{"year":2015,"claim":"Refined the synaptic mechanism by mapping the presynaptic-binding region of the intracellular domain and demonstrating its requirement for glutamate release, while linking APLP2 to NMDA receptor surface expression.","evidence":"Domain mapping with JCasp interference peptide and glutamate release in hippocampal slices; Co-IP and surface assays with GluN1/GluN2","pmids":["26551565","25683482"],"confidence":"High","gaps":["Direct binding partner within the release machinery not fully defined","NMDA receptor surface effect not tested in vivo for APLP2 specifically"]},{"year":2021,"claim":"Established a molecular pathway for APP/APLP2 in synaptic plasticity through neuronal calcium homeostasis and identified the secreted ectodomain as the functional rescue species.","evidence":"Conditional double KO neurons, Ca2+ imaging, SERCA/Stim1/2 analysis, AAV-APPsalpha rescue and LTP","pmids":["34172567"],"confidence":"High","gaps":["Receptor transducing the chronic APPsalpha rescue signal not identified","APLP2-specific contribution versus APP not separated"]},{"year":2023,"claim":"Extended APLP2 signaling beyond the nervous system, defining AICD2-driven NF-kB activation and APLP2-mediated TGFBR2 destabilization as distinct effector mechanisms.","evidence":"Co-IP of AICD2 with p65 and NF-kB reporters in macrophages; Co-IP with TGFBR2/Hsp90 plus ubiquitination and gain/loss-of-function for TGF-beta signaling","pmids":["37844466","37479189"],"confidence":"Medium","gaps":["Single-lab Co-IP evidence without reciprocal structural validation","Whether AICD2 directly binds p65 or acts via cofactors unresolved"]},{"year":2026,"claim":"Identified a receptor target for the APLP2 ectodomain, showing endothelial APLP2sα drives angiogenesis by allosteric modulation of KIT.","evidence":"Endothelial-specific KO mice, myocardial infarction model, secretase assays, KIT signaling, AAV-APPsalpha rescue","pmids":["42172320"],"confidence":"Medium","gaps":["Direct biophysical binding of APLP2sα to KIT not shown","Whether neuronal ectodomain roles also use KIT not tested"]},{"year":null,"claim":"How APLP2's many context-specific activities (synaptic, vascular, immune, oncogenic) are coordinated by a common proteolytic and trafficking logic, and which receptors transduce the soluble ectodomain in each setting, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying receptor for sAPLP2 across tissues established","APLP2-specific versus APP-shared functions not systematically separated","Structural basis of intracellular-domain partner selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,33]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[36,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[18,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17,25]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[34,19]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[18,24,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[33,34,36]}],"complexes":["APP/Mint2/Munc18 presynaptic complex","APP-APLP2 cis heteromer"],"partners":["APP","MINT2","MUNC18","GLUN1","PCSK9","TGFBR2","BAT3","CD11B"],"other_free_text":[]}},"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 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Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37479189","citation_count":3,"is_preprint":false},{"pmid":"36691315","id":"PMC_36691315","title":"APLP2 is predominantly cleaved by β-secretase and γ-secretase in the human brain.","date":"2023","source":"Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society","url":"https://pubmed.ncbi.nlm.nih.gov/36691315","citation_count":2,"is_preprint":false},{"pmid":"32716039","id":"PMC_32716039","title":"APLP2 gene polymorphisms are associated with high TC and LDL-C levels in Chinese population in Xinjiang, China.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32716039","citation_count":2,"is_preprint":false},{"pmid":"16154762","id":"PMC_16154762","title":"The amyloid-beta precursor-like protein APLP2 and its relative APP are differentially regulated during neuroendocrine cell activation.","date":"2005","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/16154762","citation_count":1,"is_preprint":false},{"pmid":"12595709","id":"PMC_12595709","title":"Crystallization and preliminary crystallographic analysis of extracellular fragment X3 of YWK-II/APPH: a human sperm membrane protein related to the Alzheimer betaA4-amyloid precursor protein.","date":"2003","source":"Acta crystallographica. 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Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/12499552","citation_count":1,"is_preprint":false},{"pmid":"16720320","id":"PMC_16720320","title":"Delineation of the functional domains of the extracellular region of YWK-II Protein/APLP2 of sperm membrane.","date":"2006","source":"Frontiers in bioscience : a journal and virtual library","url":"https://pubmed.ncbi.nlm.nih.gov/16720320","citation_count":1,"is_preprint":false},{"pmid":"42172320","id":"PMC_42172320","title":"Endothelial soluble APP/APLP2 promote heart repair through KIT-mediated angiogenesis.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/42172320","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.07.669134","title":"Sound-evoked auditory neurophysiological signals are a window into prodromal functional differences in a preclinical model of Alzheimer′s Disease","date":"2025-08-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.07.669134","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.13.659437","title":"Proteomics- and BRET-screens identify SPRY2 as Ras effector that impacts its membrane organisation","date":"2025-06-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.13.659437","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34626,"output_tokens":9394,"usd":0.122394,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19471,"output_tokens":4313,"usd":0.10259,"stage2_stop_reason":"end_turn"},"total_usd":0.224984,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"APLP2 contains a cytoplasmic domain predicted to couple with the GTP-binding protein G(o), suggesting it may function as a cell surface activator of this G protein, similar to APP.\",\n      \"method\": \"Sequence analysis and structural prediction of cloned APLP2 gene\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/structural prediction only, no direct binding experiment performed\",\n      \"pmids\": [\"8220435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"APLP2 is modified by chondroitin sulfate (CS) glycosaminoglycan addition at a single site (Ser-614); a serine-to-alanine substitution at position 614 abolishes CS GAG modification, identifying this as the sole modification site.\",\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 / Strong — in vitro mutagenesis with direct biochemical readout, clearly defined mechanism\",\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 N-terminal to Ser-614, is not modified by CS GAG, whereas APLP2-751 is. Similarly, APP isoforms lacking exon 15 sequences (L-APP) are CS GAG-modified, whereas those containing exon 15 are not.\",\n      \"method\": \"Expression of alternatively spliced isoforms in transfected cells, chondroitinase digestion, biochemical analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct mutagenesis/isoform expression with biochemical validation, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"7622456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"APLP2 is enriched in postsynaptic compartments in cortex and hippocampus, and is abundant in olfactory sensory axons and axon terminals in glomeruli; CS GAG-modified APLP2 forms are enriched in olfactory epithelium and accumulate 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\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunocytochemistry and confocal microscopy, functional implication inferred but not directly tested\",\n      \"pmids\": [\"7472397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"APLP2 and APP are functionally redundant in vivo: APLP2 single KO mice are viable and fertile, but APP/APLP2 double KO mice exhibit ~80% early postnatal lethality, demonstrating that APLP2 and APP can substitute for each other functionally.\",\n      \"method\": \"Generation of APLP2 KO and APP/APLP2 double KO mice, phenotypic analysis\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double knockout with clear phenotypic readout, widely replicated\",\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 embryos arrest before the blastocyst stage with abnormal nuclear DNA content (departing from normal 2-4C values), and antisense suppression in fibroblasts produces daughter cells with abnormal DNA contents, indicating a role in mitotic genome segregation.\",\n      \"method\": \"Generation of large genomic deletion in mice, DNA content analysis, antisense RNA transfection in fibroblasts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype (DNA content abnormality), two approaches (KO embryos + antisense), single lab\",\n      \"pmids\": [\"9707424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"APP and APLP2 expression specifically modulates copper homeostasis in the liver and cerebral cortex; APP(-/-) and APLP2(-/-) mice show significantly elevated copper levels in cerebral cortex (40% and 16%, respectively) and liver (80% and 36%, respectively) compared to wild-type, with no significant differences in zinc or iron.\",\n      \"method\": \"Atomic absorption spectrophotometry of tissue from APP(-/-) and APLP2(-/-) knockout mice\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement in KO mice with specificity for copper vs other metals, single lab\",\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 APP isoforms sAPP695 and sAPP751.\",\n      \"method\": \"Expression of recombinant sAPLP2 in Pichia pastoris, neurite outgrowth assay on chick sympathetic neurons\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with purified 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 MAP kinase (MAPK): basal shedding and that induced by PKC activator PMA or EGF is blocked by the MEK inhibitor U-0126; PKC-epsilon is involved in PMA- and EGF-induced shedding.\",\n      \"method\": \"Western blotting, flow cytometry, indirect immunofluorescence, pharmacological inhibition with U-0126 and PKC-epsilon inhibitor in human corneal epithelial cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with multiple inhibitors and multiple readout methods, single lab\",\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, producing C-terminal fragments, intracellular domains (AICD-like), and p3-like and Abeta-like fragments. BACE (beta-secretase) modulates APLP2 processing in vivo: APLP2 proteolytic products are decreased in BACE KO mice and increased in BACE transgenic mice; overexpression of BACE in cultured cells increases APLP2 processing.\",\n      \"method\": \"C-terminally tagged constructs in stably transfected SH-SY5Y cells, pharmacological inhibitors, BACE KO and transgenic mice, Western blot\",\n      \"journal\": \"The Journal of biological chemistry; Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple pharmacological inhibitors, KO and transgenic animal models, replicated across two independent studies\",\n      \"pmids\": [\"14970212\", \"15080893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APLP2 is a substrate for the disintegrin-metalloproteinases ADAM10 and TACE (ADAM17): overexpression of either proteinase in HEK293 cells increases shedding of soluble APLP2 severalfold; ADAM10-preferring inhibitor most strongly reduces shedding in neuroblastoma cells; ADAM10 transgenic mice show significantly increased soluble APLP2 and its C-terminal fragments.\",\n      \"method\": \"Overexpression of ADAM10/TACE in HEK293 cells, pharmacological inhibition in neuroblastoma cells, ADAM10 transgenic mice, Western blot\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — gain-of-function overexpression, pharmacological inhibition, and in vivo transgenic validation, multiple methods\",\n      \"pmids\": [\"16279945\"],\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 APP and both Cu(II) and Cu(I) forms of APLP2 inhibit glypican-1 autodegradation; in primary cortical neurons from APP or APLP2 KO mice, nitric oxide-catalyzed heparan sulfate degradation is increased; in APLP2 KO (but not APP KO) fibroblasts, heparan sulfate degradation is also increased.\",\n      \"method\": \"Cell-free biochemical experiments, confocal immunofluorescence microscopy, flow cytometry, primary neurons and fibroblasts from KO mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (cell-free, imaging, KO cells), clear mechanistic distinction between APP and APLP2 roles\",\n      \"pmids\": [\"15677459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PAT1a binds directly to APP, APLP1, and APLP2 in vivo and co-localizes with them in trans-Golgi network vesicles or endosomes in primary neurons; PAT1a interacts with the basolateral sorting signal of APP/APLPs; overexpression or RNAi knockdown of PAT1a modulates APP/APLP surface levels and promotes their processing, resulting in increased Abeta secretion.\",\n      \"method\": \"Co-immunoprecipitation, co-localization in primary neurons, overexpression and RNAi knockdown, cell surface assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, co-localization, gain- and loss-of-function with functional readouts, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"17050537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"APP and APLP2 are required for keratinocyte proliferation, migration, and adhesion: keratinocytes from APP/APLP2 double KO mice show ~40% reduced proliferation in vivo and in vitro, reduced migration velocity, and compromised cell-substrate adhesion; double KO keratinocytes die within the first week of culture. Proliferation deficits are rescued by exogenous recombinant sAPPalpha.\",\n      \"method\": \"KO mouse keratinocyte isolation, proliferation assays, migration assays, rescue with recombinant sAPPalpha\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined phenotypic readouts and rescue experiment, single lab\",\n      \"pmids\": [\"16584729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APP and APLP2 are required for normal glucose and insulin homeostasis: APP/APLP2 double KO mice show 66% lower plasma glucose and hyperinsulinemia compared to wild-type at postnatal day, identifying a role for APP/APLP2 in modulating plasma insulin and glucose concentrations.\",\n      \"method\": \"Plasma analysis from double KO mice at E17 and postnatal, glucose and insulin measurements\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical measurement in KO mice with specific metabolic readout, single lab\",\n      \"pmids\": [\"18393365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of APP and APLP2 in neurons leads to decreased expression of vesicular glutamate transporter 2 (VGLUT2) and reduced glutamate uptake/release; blocking gamma-secretase in wild-type neurons similarly decreases VGLUT2; VGLUT2 levels can be restored in double KO neurons by a construct encoding the C-terminal intracellular domain of APP, indicating the intracellular domain mediates this function.\",\n      \"method\": \"ESC-derived neurons from APP/APLP2 double KO mice, VGLUT2 mRNA and protein quantification, gamma-secretase inhibition, APP intracellular domain rescue construct, electrophysiology in hippocampal slices\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (KO neurons, pharmacological inhibition, rescue construct, electrophysiology), mechanistic pathway defined\",\n      \"pmids\": [\"18535156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"APLP2 and APP share overlapping anticoagulant functions: recombinant KPI domains of both proteins inhibit plasma clotting in vitro; APLP2(-/-) and APP(-/-) mice both exhibit significantly shorter times to carotid artery occlusion and produce smaller hematomas in intracerebral hemorrhage models, indicating a prothrombotic phenotype when APLP2 is absent.\",\n      \"method\": \"Recombinant KPI domain inhibition assays, carotid artery thrombosis model, intracerebral hemorrhage model in KO mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemical assay plus two in vivo KO models with defined functional readouts\",\n      \"pmids\": [\"19403832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Live cell imaging shows that APLP2 localizes predominantly to intracellular compartments (unlike APLP1 which is mainly at the cell surface); APLP2 forms homo- and heterotypic cis interactions with APP family members detectable by FRET and co-immunoprecipitation; interactions occur in a modular mode with the N-terminal half of the ectodomain crucial for APP-APLP2 interactions; coexpression of APP with 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 1–2 / Strong — multiple orthogonal methods (live imaging, FRET, Co-IP, deletion mutants) with functional readout (Abeta42 generation)\",\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 mice (expressing only secreted APPsα on APLP2-null background) show impaired neuromuscular transmission with reductions in quantal content, readily releasable pool, and vesicle release sustainability, resulting in muscular weakness; defects are associated with loss of an APP/Mint2/Munc18 complex; APPsα-DM muscle shows fragmented postsynaptic specializations.\",\n      \"method\": \"APPsα knock-in mice crossed onto APLP2-deficient background, electrophysiology, co-immunoprecipitation of APP/Mint2/Munc18 complex, morphological analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic rescue experiment with defined physiological readout, Co-IP of complex, morphological and electrophysiological validation\",\n      \"pmids\": [\"21522131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"APLP2 mediates signaling via formation of transcriptionally active triple protein complexes with adaptor protein Mint3 and transcriptional co-activators Taz and Yap; complex formation is regulated by gamma-secretase cleavage of APLP2; Mint1 (instead of Mint3) prevents nuclear translocation of the complex.\",\n      \"method\": \"Co-immunoprecipitation, transactivation assays, gamma-secretase inhibition\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and functional transactivation assays, single lab, multiple complex members identified\",\n      \"pmids\": [\"21178287\"],\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 KO background causes cortical progenitors to remain undifferentiated longer with a higher number of mitotic cells; neuron-specific APLP2 downregulation does not affect the speed or position of migrating excitatory cortical neurons.\",\n      \"method\": \"shRNA-mediated APLP2 silencing in vivo in APP/APLP1 double KO mice, analysis of mitotic cells and neuronal differentiation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with specific cellular phenotype, defined genetic background, single lab\",\n      \"pmids\": [\"23345401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PCSK9 interacts directly with APLP2 (but not APP) via its C-terminal domain in a pH-dependent manner; APLP2 (but not APP) mediates postendocytic delivery of PCSK9 to lysosomes, making it required for PCSK9 function in LDLR degradation.\",\n      \"method\": \"Co-immunoprecipitation, pH-dependent binding assays, cell-based PCSK9 trafficking assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with functional readout (lysosomal delivery), single lab, direct binding demonstrated\",\n      \"pmids\": [\"23430252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APLP2 co-immunoprecipitates with MHC class I molecules in Ewing's sarcoma cells; irradiation redistributes APLP2 and MHC class I on the cell surface; APLP2 siRNA knockdown increases MHC class I surface expression, indicating APLP2 inhibits MHC class I surface expression.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry, siRNA knockdown\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and loss-of-function with defined functional readout, single lab\",\n      \"pmids\": [\"24353913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"APP/APLP2 expression is required for transport of anhydromannose-containing heparan sulfate from endosomes to the nucleus and subsequently to autophagosomes: nuclear HS translocation is seen in WT but not APP(-/-) or APLP2(-/-) MEFs; transfection of APP restores nuclear import; beta- and gamma-secretase inhibitors block nuclear transport, implicating APP/APLP2 degradation products.\",\n      \"method\": \"Deconvolution immunofluorescence microscopy with anMan-specific antibody, 35S-labeling, secretase inhibitor treatment, APP(-/-) and APLP2(-/-) MEFs, transfection rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (imaging, labeling, KO, rescue), single lab\",\n      \"pmids\": [\"24898256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APP and APLP2 interact with the synaptic release machinery via the NH2-terminal region of their intracellular domains; a peptide (JCasp) naturally produced by gamma-secretase/caspase double-cut of APP interferes with APP-presynaptic protein interactions and reduces glutamate release in hippocampal slices from wild-type but not APP-deficient mice; deletion of APP and APLP2 produces synaptic deficits similar to those caused by JCasp.\",\n      \"method\": \"Mapping of binding domain, JCasp cell-penetrating peptide treatment, glutamate release assay in acute hippocampal slices, APP/APLP2 double KO comparison\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mapping, specific peptide interference, multiple genetic controls (KO vs WT), clear functional readout\",\n      \"pmids\": [\"26551565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APLP2 co-immunoprecipitates with NMDA receptor subunits GluN1/GluN2A and GluN1/GluN2B in mammalian cells and in adult brain; interaction is via GluN1 subunit; APLP2 enhances GluN1/GluN2A and GluN1/GluN2B cell surface expression.\",\n      \"method\": \"Co-immunoprecipitation from transfected cells and adult brain lysates, cell surface expression assays\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP in cells and native brain tissue, functional surface expression assay, single lab\",\n      \"pmids\": [\"25683482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APLP2 knockdown in pancreatic cancer cells reduces migration and invasion, decreases cortical actin, and increases intracellular actin filaments; APLP2 knockdown reduces tumor weight and metastasis in orthotopic mouse models, indicating APLP2 affects actin cytoskeleton organization to promote cancer cell migration.\",\n      \"method\": \"Inducible shRNA knockdown, migration/invasion assays, actin cytoskeleton imaging, orthotopic tumor transplantation in mice\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular and in vivo phenotypes, single lab\",\n      \"pmids\": [\"25576918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Aplp2 knockout mice develop high degrees of hyperopia and exhibit dose-dependent reduction in susceptibility to environmentally induced myopia; the 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, contrast sensitivity testing, retinal electrophysiology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotyping with multiple functional readouts, single lab\",\n      \"pmids\": [\"26313004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APP, APLP2, and LRP1 all interact with PCSK9, but none is required for PCSK9-mediated LDLR degradation in vivo: infusion of PCSK9 into App(-/-), Aplp2(-/-), Aplp2-depleted App(-/-), or liver-specific Lrp1(-/-) mice results in similar reductions in hepatic LDLR as in wild-type mice.\",\n      \"method\": \"Co-immunoprecipitation, PCSK9 infusion into multiple KO mouse lines, hepatic LDLR measurement\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with direct functional readout, negative result for APLP2 requirement in LDLR degradation is mechanistically informative; contradicts PMID 23430252 partial conclusion\",\n      \"pmids\": [\"28495363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"APLP2 promotes cell migration in Drosophila via JNK signaling: ectopic APLP2 expression activates JNK by phosphorylation, which triggers MMP1 expression required for basement membrane degradation and cell migration; loss of JNK suppresses APLP2-induced migration while gain of JNK enhances it.\",\n      \"method\": \"Drosophila ectopic expression, JNK loss- and gain-of-function epistasis, phosphorylation assays, MMP1 expression analysis\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Drosophila model organism with defined pathway, consistent with mammalian context but in Drosophila\",\n      \"pmids\": [\"30155482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of APP and APLP2 specifically in GABAergic forebrain neurons (DlxCre cDKO) impairs synaptic plasticity (LTP), spatial learning, and excitation/inhibition balance; reduced action potential firing of CA1 pyramidal cells and altered excitatory/inhibitory synaptic currents indicate APP family proteins in inhibitory interneurons maintain functional network activity.\",\n      \"method\": \"Conditional double KO using DlxCre, electrophysiology (LTP, synaptic currents), behavioral testing, morphological analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with multiple orthogonal readouts (electrophysiology, behavior, morphology), single lab but rigorous\",\n      \"pmids\": [\"32219307\"],\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, ER Ca2+ store refill, and synaptic plasticity via altered SERCA-ATPase function and expression of store-operated Ca2+ channel-associated proteins Stim1 and Stim2; long-term AAV-mediated expression of APPsα (but not acute application) restores Ca2+ homeostasis and LTP in APP/APLP2 cDKO neurons.\",\n      \"method\": \"APP/APLP2 conditional double KO neurons, Ca2+ imaging, SERCA-ATPase and Stim1/Stim2 expression analysis, AAV-mediated APPsα rescue, LTP recordings\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO with specific molecular mechanism (SERCA, Stim1/2), genetic rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"34172567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Peripheral nerve injury reduces APLP2 expression specifically in spinal GABAergic inhibitory interneurons; targeted knockdown of APLP2 in GAD2-positive neurons evokes pain hypersensitivity via microglial activation; APLP2 at GABAergic terminals interacts with microglia-specific integrin CD11b in a trans-cellular manner, and disruption of this interaction leads to microglia-dependent pain sensitization.\",\n      \"method\": \"Nerve injury model, conditional APLP2 knockdown in GAD2-Cre mice, co-immunoprecipitation of APLP2 with CD11b, pain behavioral testing, microglial activation assays\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — cell-type-specific KD with defined phenotype and Co-IP of binding partner, single lab\",\n      \"pmids\": [\"36442651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"APLP2 (as YWK-II/APLP2) inhibits TGF-β signaling by promoting degradation of TGFBR2: APLP2 associates with TGFBR2 in a TGF-β activity-dependent manner, binds Hsp90 to interfere with the TGFBR2-Hsp90 stabilizing interaction, and leads to enhanced ubiquitination and degradation of TGFBR2; knockdown of APLP2 increases TGFBR2 protein level and sensitizes cells to TGF-β, while overexpression destabilizes TGFBR2.\",\n      \"method\": \"Co-immunoprecipitation, knockdown and overexpression experiments, ubiquitination assays, TGF-β signaling readouts\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with Hsp90 and TGFBR2, gain/loss-of-function with functional readout, mechanistic model supported by multiple assays, single lab\",\n      \"pmids\": [\"37479189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The APLP2 cleaved intracellular domain product (AICD2), generated by gamma-secretase, translocates to the nucleus where it interacts with p65, enhancing NF-κB transcriptional activity to upregulate IL-1β and iNOS expression; APLP2 mutation/knockdown reduces macrophage-mediated killing of Mycobacterium tuberculosis.\",\n      \"method\": \"Aplp2 mutant/knockdown macrophages, nuclear translocation assay, co-immunoprecipitation with p65, NF-κB reporter assays, iNOS and IL-1β measurement, M.tb infection in KO mice\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of AICD2 with p65, multiple loss-of-function approaches and in vivo KO, single lab\",\n      \"pmids\": [\"37844466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bat3 interacts with APLP2 (YWK-II/APLP2) and enhances its stability by reducing ubiquitylation and proteasomal degradation; the proline-rich domain of Bat3 is required for binding to APLP2; nuclear export of Bat3 under apoptotic stimulation elevates APLP2 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion analysis, ubiquitylation assays, apoptosis stimulation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with domain mapping, ubiquitylation assay, single lab\",\n      \"pmids\": [\"22641691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Endothelial APLP2 is required for postischemia angiogenesis after myocardial infarction; hypoxia induces alpha-secretase-mediated processing of APLP2 into soluble APLP2sα; APPsα and APLP2sα exert proangiogenic effects by positive allosteric modulation of the endothelial receptor tyrosine kinase KIT, promoting neovascularization.\",\n      \"method\": \"Endothelial-specific APP/APLP2 knockout mice, myocardial infarction model, secretase activity assays, KIT receptor signaling assays, AAV rescue with APPsα\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with in vivo functional readout, defined molecular mechanism (KIT allosteric modulation), genetic rescue, single lab\",\n      \"pmids\": [\"42172320\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"APLP2 is a type I transmembrane glycoprotein and APP paralog that is processed by alpha-, beta-, gamma-, and epsilon-secretases (with BACE/beta-secretase predominating in the CNS) and by ADAM10/TACE metalloproteases to release a neurotrophic soluble ectodomain (APLP2sα) and an intracellular domain (AICD2); APLP2 and APP are functionally redundant during postnatal development (double KO mice die perinatally), and together mediate neuromuscular and hippocampal synaptic transmission, spatial learning, and LTP through interactions with the synaptic release machinery (Mint2/Munc18 complex) and NMDA receptors; APLP2 modulates copper homeostasis, acts as a Kunitz-type serine protease inhibitor to regulate cerebral thrombosis, controls neuronal Ca²⁺ homeostasis via SERCA-ATPase and Stim1/2, regulates glypican-1 heparan sulfate catabolism, and its AICD2 fragment activates NF-κB signaling via p65; APLP2 is subject to post-translational regulation including CS glycosaminoglycan modification at Ser-614 (regulated by alternative splicing), ubiquitin-proteasome degradation stabilized by Bat3, and ectodomain shedding regulated by MAPK/PKC signaling; outside the nervous system, APLP2 promotes pancreatic cancer cell migration by reorganizing the actin cytoskeleton, inhibits TGF-β signaling by destabilizing TGFBR2 via competition with Hsp90, modulates MHC class I surface expression, maintains GABAergic interneuron-microglia interactions at the synapse, and endothelial APLP2sα drives postischemic angiogenesis through allosteric activation of the KIT receptor tyrosine kinase.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"APLP2 is a type I transmembrane glycoprotein of the APP family that functions in synaptic transmission, neural development, and diverse cell-surface signaling processes, acting largely redundantly with APP [#4]. Like APP, APLP2 undergoes sequential proteolytic processing by alpha- and beta-secretases—with BACE modulating its cleavage in vivo [#9]—and by the metalloproteinases ADAM10 and TACE to shed a soluble neurotrophic ectodomain [#10, #7], followed by gamma-/epsilon-secretase cleavage that liberates an intracellular domain (AICD2) [#9]; ectodomain shedding is controlled by MAPK/PKC-epsilon signaling [#8]. APLP2 and APP are functionally redundant during postnatal development, with double knockout causing early lethality [#4], and together they sustain neuromuscular and central synaptic transmission: they bind the presynaptic release machinery via the N-terminus of their intracellular domains in a complex with Mint2/Munc18 to support quantal glutamate release [#18, #24], interact with NMDA receptor GluN1 to promote receptor surface expression [#25], control VGLUT2 expression through the intracellular domain [#15], and maintain neuronal Ca2+ homeostasis through SERCA-ATPase and Stim1/2 [#31]. APP family loss in GABAergic interneurons impairs LTP, spatial learning, and excitation/inhibition balance [#30], and APLP2 at GABAergic terminals engages microglial CD11b in trans to restrain pain sensitization [#32]. APLP2 forms homo- and heterotypic cis complexes with APP, reducing Abeta42 generation [#17], and is subject to post-translational regulation including chondroitin-sulfate modification at Ser-614 governed by alternative splicing [#1, #2] and Bat3-mediated stabilization against proteasomal degradation [#35]. APLP2 also modulates copper homeostasis [#6], inhibits plasma clotting through its Kunitz-type protease inhibitor domain [#16], and regulates glypican-1 heparan sulfate catabolism [#11]. Outside the nervous system, APLP2 promotes pancreatic cancer cell migration via actin reorganization [#26], inhibits TGF-beta signaling by destabilizing TGFBR2 through competition with Hsp90 [#33], suppresses MHC class I surface expression [#22], and its AICD2 fragment activates NF-kB via p65 to drive antimicrobial macrophage responses [#34]; endothelial APLP2s\\u03b1 promotes postischemic angiogenesis through allosteric activation of the KIT receptor [#36].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the first defined post-translational modification of APLP2, pinpointing a single chondroitin-sulfate attachment site that would distinguish APLP2 proteoglycan forms.\",\n      \"evidence\": \"Site-directed mutagenesis (Ser614Ala) and chondroitinase digestion in transfected CHO/COS cells\",\n      \"pmids\": [\"8071334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CS-GAG modification not addressed\", \"Does not connect modification to a downstream signaling or trafficking event\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed that CS-GAG modification of APLP2 is switched by alternative splicing, defining a regulated mechanism for generating proteoglycan versus non-proteoglycan APLP2 isoforms.\",\n      \"evidence\": \"Isoform expression and chondroitinase analysis of APLP2-751 vs APLP2-763 in transfected cells\",\n      \"pmids\": [\"7622456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of each isoform unresolved\", \"Tissue-specific splicing regulation not mapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved whether APLP2 has an essential individual function by revealing functional redundancy with APP, a foundational genetic insight for the family.\",\n      \"evidence\": \"APLP2 single KO and APP/APLP2 double KO mouse phenotyping\",\n      \"pmids\": [\"9461064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of redundancy not defined\", \"Specific lethal process in double KO not identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected APLP2 to metal handling and to neurotrophic ectodomain activity, broadening its role beyond development.\",\n      \"evidence\": \"Tissue copper measurement in KO mice and neurite outgrowth assay with recombinant sAPLP2\",\n      \"pmids\": [\"10526140\", \"9923612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct copper-binding mechanism of APLP2 not shown\", \"Receptor mediating sAPLP2 neurite outgrowth unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the proteolytic machinery acting on APLP2, establishing that it is processed analogously to APP by BACE, ADAM10/TACE, and gamma/epsilon-secretases.\",\n      \"evidence\": \"Tagged constructs in neuroblastoma cells, secretase overexpression, pharmacological inhibition, and BACE/ADAM10 KO and transgenic mice\",\n      \"pmids\": [\"14970212\", \"15080893\", \"16279945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signaling output of each fragment not fully resolved\", \"Regulation of cleavage site choice in vivo not detailed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished APP from APLP2 in heparan sulfate metabolism, showing APLP2 regulates copper/NO-catalyzed glypican-1 autodegradation.\",\n      \"evidence\": \"Cell-free copper-form assays, imaging, and KO neurons and fibroblasts\",\n      \"pmids\": [\"15677459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of glypican-1 regulation unclear\", \"Link between this activity and synaptic/developmental roles not made\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated APLP2 forms cis homo- and heteromeric complexes with APP and exerts anticoagulant activity, two distinct mechanistic roles for the protein.\",\n      \"evidence\": \"FRET, Co-IP, deletion mutants for complex formation; recombinant KPI assays and thrombosis/hemorrhage KO models for anticoagulation\",\n      \"pmids\": [\"19126676\", \"19403832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and physiological abundance of heteromers unknown\", \"Protease target of the KPI domain in vivo not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the synaptic mechanism by which APLP2/APP support neurotransmission, linking the intracellular domain to the Mint2/Munc18 release machinery.\",\n      \"evidence\": \"APPsalpha knock-in on APLP2-null background, electrophysiology, Co-IP of APP/Mint2/Munc18 complex\",\n      \"pmids\": [\"21522131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APLP2 intracellular domain binds the complex identically to APP not separated\", \"Direct versus adaptor-mediated binding not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined the synaptic mechanism by mapping the presynaptic-binding region of the intracellular domain and demonstrating its requirement for glutamate release, while linking APLP2 to NMDA receptor surface expression.\",\n      \"evidence\": \"Domain mapping with JCasp interference peptide and glutamate release in hippocampal slices; Co-IP and surface assays with GluN1/GluN2\",\n      \"pmids\": [\"26551565\", \"25683482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner within the release machinery not fully defined\", \"NMDA receptor surface effect not tested in vivo for APLP2 specifically\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a molecular pathway for APP/APLP2 in synaptic plasticity through neuronal calcium homeostasis and identified the secreted ectodomain as the functional rescue species.\",\n      \"evidence\": \"Conditional double KO neurons, Ca2+ imaging, SERCA/Stim1/2 analysis, AAV-APPsalpha rescue and LTP\",\n      \"pmids\": [\"34172567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor transducing the chronic APPsalpha rescue signal not identified\", \"APLP2-specific contribution versus APP not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended APLP2 signaling beyond the nervous system, defining AICD2-driven NF-kB activation and APLP2-mediated TGFBR2 destabilization as distinct effector mechanisms.\",\n      \"evidence\": \"Co-IP of AICD2 with p65 and NF-kB reporters in macrophages; Co-IP with TGFBR2/Hsp90 plus ubiquitination and gain/loss-of-function for TGF-beta signaling\",\n      \"pmids\": [\"37844466\", \"37479189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP evidence without reciprocal structural validation\", \"Whether AICD2 directly binds p65 or acts via cofactors unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a receptor target for the APLP2 ectodomain, showing endothelial APLP2s\\u03b1 drives angiogenesis by allosteric modulation of KIT.\",\n      \"evidence\": \"Endothelial-specific KO mice, myocardial infarction model, secretase assays, KIT signaling, AAV-APPsalpha rescue\",\n      \"pmids\": [\"42172320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biophysical binding of APLP2s\\u03b1 to KIT not shown\", \"Whether neuronal ectodomain roles also use KIT not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How APLP2's many context-specific activities (synaptic, vascular, immune, oncogenic) are coordinated by a common proteolytic and trafficking logic, and which receptors transduce the soluble ectodomain in each setting, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying receptor for sAPLP2 across tissues established\", \"APLP2-specific versus APP-shared functions not systematically separated\", \"Structural basis of intracellular-domain partner selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 33]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [36, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [18, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17, 25]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [34, 19]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [18, 24, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [33, 34, 36]}\n    ],\n    \"complexes\": [\n      \"APP/Mint2/Munc18 presynaptic complex\",\n      \"APP-APLP2 cis heteromer\"\n    ],\n    \"partners\": [\n      \"APP\",\n      \"Mint2\",\n      \"Munc18\",\n      \"GluN1\",\n      \"PCSK9\",\n      \"TGFBR2\",\n      \"Bat3\",\n      \"CD11b\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}