Affinage

APP

Amyloid-beta precursor protein · UniProt P05067

Length
770 aa
Mass
86.9 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APP is a type I transmembrane glycoprotein whose proteolytic processing and intracellular trafficking govern neuronal survival, synaptic function, migration, and amyloid-β (Aβ) production (PMID:22884903, PMID:17873282). APP is cleaved along competing pathways: α-secretase activity, contributed by ADAM9, ADAM10, and ADAM17 and coupled to neuronal PKCα activation, releases the trophic ectodomain sAPPα, which supports dendritic spine density and long-term potentiation (PMID:12535668, PMID:22884903, PMID:10858291), whereas β-secretase (BACE1) and γ-secretase generate Aβ and the APP-βCTF (C99) fragment, the latter raising lysosomal pH and inactivating cathepsin D to drive lysosomal dysfunction (PMID:31043483). Which pathway predominates is set by APP trafficking and conformation: phosphorylation at Y687 and S655 directs APP between endocytic and secretory routes (PMID:17873282, PMID:19381782), cis-dimerization—initiated by ER disulfide bonds in the E1 domain and promoted by palmitoylation via DHHC7/DHHC21—favors BACE1 cleavage (PMID:22105709, PMID:27875558), and APP–BACE1 proximity is modulated by cholesterol binding (PMID:33296223, PMID:18374657). Sorting adaptors and trafficking machinery including PAT1a, retromer (Vps35), and Rab35 (acting through effectors ACAP2 and OCRL) partition APP and BACE1 to limit amyloidogenic processing, while HTT-dependent axonal transport delivers APP to presynaptic terminals (PMID:17050537, PMID:21515373, PMID:34876559, PMID:32452382). The γ-secretase product AICD acts as a transcriptional co-activator: with FE65 it transduces the extracellular ligand TAG1 to suppress neurogenesis, with FoxO it induces the pro-apoptotic gene Bim under oxidative stress, and it directly regulates the WAVE1/Wasf1 and JNK3 loci to control vesicular APP trafficking and neuronal death (PMID:18278038, PMID:26280122, PMID:24832605, PMID:29238071). At the cell surface APP engages partners including TAG1, Synaptotagmins, BRI2, TrkA, and the CD74/CXCR4 complex to couple extracellular signals to processing, survival, and—in glioblastoma—inhibition of macrophage phagocytosis (PMID:18278038, PMID:16027166, PMID:21849536, PMID:26202512, PMID:39111632). APP expression is further tuned post-transcriptionally by the mRNA-binding proteins hnRNP C and HuD and transcriptionally by an ApoE-driven DLK→MKK7→ERK→AP-1 cascade and p53/Sp1 promoter regulation (PMID:9649628, PMID:24857657, PMID:28111074, PMID:19049493).

Mechanistic history

Synthesis pass · year-by-year structured walk · 34 steps
  1. 1998 Medium

    Established that APP abundance is controlled post-transcriptionally, identifying hnRNP C as a stabilizing 3'-UTR binder long before APP's many regulatory inputs were mapped.

    Evidence In vitro reticulocyte lysate translation with cis-element mutagenesis and RNA gel shift

    PMID:9649628

    Open questions at the time
    • Whether hnRNP C regulates APP in neurons in vivo not addressed
    • Does not link expression level to Aβ output
  2. 2000 Medium

    Defined PKCα as the kinase isoform coupling PKC activation to regulated sAPP (α-secretase) secretion in neurons, connecting signaling to the non-amyloidogenic pathway.

    Evidence Isoform-selective PKC downregulation and pharmacological inhibition in human NT2N neurons with sAPP ELISA

    PMID:10858291

    Open questions at the time
    • Direct phosphorylation target of PKCα on APP/secretase not identified
    • Mechanism linking PKCα to ADAM activity unresolved
  3. 2001 Medium

    Showed APP, with FE65, localizes to motility structures and accelerates cell migration, establishing a non-amyloid cell-biological role at focal complexes.

    Evidence Immunofluorescence co-localization and MDCK wound-healing migration assay with co-expression

    PMID:11425871

    Open questions at the time
    • Molecular basis of migration enhancement (integrin signaling vs surface level) unclear
    • Relevance to neuronal migration in vivo not tested
  4. 2001 Medium

    Tested whether caspase cleavage of the APP tail drives amyloidogenesis, finding it instead removes the endocytosis signal and reduces Aβ—a negative result constraining apoptosis-amyloid models.

    Evidence Caspase-site-masked APP mutants and serum-withdrawal caspase activation with internalization and Aβ readouts

    PMID:11397796

    Open questions at the time
    • Physiological role of caspase-cleaved APP fragment undefined
    • Single-cell-line context
  5. 2003 Medium

    Identified ADAM9/10/17 as the collective endogenous α-secretase, defining the enzymatic basis of the non-amyloidogenic cleavage.

    Evidence Overexpression in COS-7 and dsRNA knockdown of each ADAM in A172 cells measuring α-secretase activity

    PMID:12535668

    Open questions at the time
    • Relative contribution of each ADAM in neurons not resolved
    • Regulation of ADAM access to APP not addressed
  6. 2003 Medium

    Linked neuronal activity to Aβ production and demonstrated Aβ depresses excitatory transmission via NMDA receptors, proposing an activity-dependent negative-feedback role.

    Evidence Hippocampal slice electrophysiology with APP overexpression and NMDA receptor blockade

    PMID:12670422

    Open questions at the time
    • Molecular coupling of activity to secretase access undefined
    • Physiological vs pathological Aβ concentrations not delineated
  7. 2003 Medium

    Connected APP to neuronal apoptosis through APP-BP1 binding the C31 tail and a NEDD8-conjugation requirement, implicating ubiquitin-like signaling in APP-induced death.

    Evidence Co-IP, lipid raft fractionation, dominant-negative hUbc12, and neuronal apoptosis assay

    PMID:14557245

    Open questions at the time
    • NEDD8 substrate driving apoptosis not identified
    • Relationship to AICD-dependent death pathways unclear
  8. 2004 Medium

    Placed APP family members in Notch signaling during neuronal fate determination via Numb, expanding APP function into developmental cell-fate control.

    Evidence Drosophila transgenics and genetic epistasis across APP/APLP1/APLP2/APPL

    PMID:15385958

    Open questions at the time
    • Direct biochemical link between APP and Notch components missing
    • Conservation in mammalian neurogenesis untested here
  9. 2005 Medium

    Identified BRI2 as a cis-membrane transmembrane partner that shifts APP toward β-cleavage, an early example of a membrane partner steering processing.

    Evidence Reciprocal co-IP with transmembrane-domain deletion mapping and processing-product measurement

    PMID:16027166

    Open questions at the time
    • In vivo neuronal relevance of BRI2-APP processing effect not shown
    • Mechanism by which complex favors BACE1 access unclear
  10. 2006 Medium

    Defined PAT1a as a TGN/endosomal adaptor binding APP's basolateral sorting signal and controlling surface levels and Aβ output, mechanistically linking sorting to processing.

    Evidence In vivo co-IP, primary neuron co-localization, bidirectional RNAi/overexpression with surface and Aβ readouts

    PMID:17050537

    Open questions at the time
    • Structural basis of sorting-signal recognition undefined
    • Interplay with other adaptors not resolved
  11. 2007 Medium

    Demonstrated that Tyr687 phosphorylation status dictates APP endocytosis and choice of processing pathway, establishing a PTM switch for amyloidogenesis.

    Evidence Y687E/Y687F phosphomutant APP-GFP with live imaging, transferrin co-localization, and Aβ ELISA

    PMID:17873282

    Open questions at the time
    • Kinase/phosphatase controlling Y687 not identified
    • In vivo significance not tested
  12. 2008 High

    Identified TAG1 as an extracellular ligand triggering γ-secretase/AICD release and Fe65-dependent suppression of neurogenesis, defining a receptor-like signaling axis for APP.

    Evidence Co-IP, genetic epistasis across TAG1/APP/Fe65 knockouts, and AICD-domain-mutant rescue in neural precursors

    PMID:18278038

    Open questions at the time
    • Structural basis of TAG1-APP binding undefined
    • Generalization beyond neurogenesis not addressed
  13. 2008 Low

    Localized APP-BACE1 encounter to intracellular compartments rather than the cell surface and showed cholesterol modulates this proximity.

    Evidence Time-resolved FRET with TIRF microscopy in living cells plus cholesterol manipulation and sAPP readout

    PMID:18374657

    Open questions at the time
    • Single-lab proximity imaging with limited functional validation
    • Specific compartment not identified
  14. 2009 Medium

    Established PKC-mediated S655 phosphorylation as a positive regulator of APP secretory exit from the Golgi favoring α-cleavage, complementing the Y687 switch.

    Evidence S655 phosphomimetic APP695-GFP mutants with Golgi dynamics imaging and sAPP quantification

    PMID:19381782

    Open questions at the time
    • Direct kinase identity and link to PKCα not established
    • In vivo effect on Aβ not measured
  15. 2009 Medium

    Showed p53 represses the APP promoter by displacing Sp1, linking the DNA-damage response to APP transcription.

    Evidence Promoter deletion constructs, EMSA, ChIP, dominant-negative p53, and camptothecin treatment

    PMID:19049493

    Open questions at the time
    • Neuronal/in vivo relevance not tested
    • Physiological trigger for p53 control of APP unclear
  16. 2011 Medium

    Defined sAPPα as the mediator of APP's trophic role at synapses, with APP knockout reducing spine density, arborization, and LTP and sAPPα rescuing spines.

    Evidence APP knockout mouse, hippocampal culture, in vivo spine counting, LTP electrophysiology, and sAPPα rescue

    PMID:22884903

    Open questions at the time
    • sAPPα receptor mediating spine maintenance not identified
    • Partial rescue implies additional APP-dependent factors
  17. 2011 Medium

    Linked APP to NGF/TrkA neurotrophic signaling, showing TrkA phosphorylates APP at Y682 and APP reciprocally regulates TrkA distribution and NGF sensitivity.

    Evidence Co-IP, phosphospecific antibodies, and Y682 knock-in mice with neurotrophic survival assays

    PMID:21849536

    Open questions at the time
    • Whether Y682 and Y687 events are coupled not resolved
    • Downstream survival effectors not mapped
  18. 2011 Medium

    Showed APP dimerization is initiated in the ER via E1-domain disulfide bonds and modulated by the KPI domain, establishing the structural origin of dimer-dependent processing.

    Evidence Organelle-retention constructs, non-reducing SDS-PAGE, E1 deletion mutants, and split-GFP in CHO-K1

    PMID:22105709

    Open questions at the time
    • Functional consequence of ER dimerization for Aβ not directly tested here
    • Isoform-specific dimerization in neurons not shown
  19. 2011 Low

    Implicated retromer in limiting amyloidogenic processing, with Vps35 loss raising Aβ42:Aβ40 and APP CTFs in exosomes.

    Evidence siRNA knockdown of Vps35 in HEK-293/APP695 with Aβ ELISA and exosome Western blot

    PMID:21515373

    Open questions at the time
    • Single-gene knockdown, single method per endpoint
    • Neuronal/in vivo confirmation lacking
  20. 2012 Low

    Identified a FE65-bridged APP–VLDLR trimeric complex altering trafficking and processing of both proteins.

    Evidence GST pull-down and co-IP in COS7 and brain lysates with processing assays

    PMID:22429478

    Open questions at the time
    • Limited mechanistic detail and single-lab data
    • Functional consequence for Aβ in vivo unresolved
  21. 2014 Medium

    Established AICD as a FoxO co-activator that induces pro-apoptotic Bim under oxidative stress, defining a transcriptional route for APP-induced cell death.

    Evidence Drosophila genetic screen, AICD-FoxO co-IP, nuclear fractionation, and Bim luciferase reporter

    PMID:24832605

    Open questions at the time
    • Relative contribution vs Fe65-dependent AICD targets unclear
    • Stress threshold for nuclear translocation undefined
  22. 2014 Medium

    Showed HuD post-transcriptionally stabilizes both APP and BACE1 mRNAs, coordinately raising Aβ in vivo.

    Evidence RNA immunoprecipitation, mRNA half-life measurement, and HuD-overexpressing transgenic mice

    PMID:24857657

    Open questions at the time
    • Upstream control of HuD activity not addressed
    • Direct vs indirect BACE1 effect on Aβ not separated
  23. 2014 High

    Demonstrated that C99 multimerization impedes γ-secretase cleavage and that primary sequence sets processivity independent of dimerization, refining how Aβ length is determined.

    Evidence Recombinant C100 substrates with isolated multimeric forms in in vitro γ-secretase assays

    PMID:25350374

    Open questions at the time
    • Cellular regulation of C99 multimer state unknown
    • Link to dimerization machinery (palmitoylation) not bridged here
  24. 2014 Medium

    Identified DISC1 as a direct APP partner controlling surface expression and internalization, shifting processing toward α-cleavage.

    Evidence RNAi in cortical neurons, co-IP, surface biotinylation, and APP-binding-domain-deletion rescue

    PMID:25224257

    Open questions at the time
    • Trafficking step targeted by DISC1 not pinpointed
    • In vivo relevance to Aβ not tested
  25. 2015 High

    Defined a reciprocal AICD–WAVE1 circuit: AICD represses Wasf1 transcription while WAVE1 promotes APP vesicle budding and surface levels, with WAVE1 reduction rescuing AD-model memory.

    Evidence ChIP, co-IP, vesicle budding assay, Aβ ELISA, and in vivo Wasf1 reduction with behavior

    PMID:26280122

    Open questions at the time
    • Whether the feedback loop is engaged under physiological conditions unclear
    • Spatial coordination of budding step undefined
  26. 2015 Medium

    Identified Synaptotagmins (Syt-1/2/9) as in vivo APP partners binding the E1-KPI linker and modulating BACE1-mediated Aβ generation.

    Evidence Brain affinity-purification MS, in vivo co-IP, GST domain mapping, and bidirectional Syt perturbation with Aβ ELISA

    PMID:26202512

    Open questions at the time
    • Mechanism by which Syt promotes BACE1 access unresolved
    • Link to synaptic vesicle cycle vs processing not separated
  27. 2016 Medium

    Connected APP palmitoylation to dimer formation and β-cleavage, with DHHC7/DHHC21 driving palmitoylated dimers in detergent-resistant membranes preferred by BACE1.

    Evidence FLIM/FRET, co-IP, DHHC7/21 overexpression, palmitoylation inhibitors, and in vitro BACE1 assay on palAPP

    PMID:27875558

    Open questions at the time
    • In vivo significance of palmitoylation-driven amyloidogenesis untested
    • Depalmitoylation enzymes not identified
  28. 2017 High

    Defined an ApoE-driven DLK→MKK7→ERK→AP-1 cascade that transcriptionally upregulates APP and Aβ with ApoE4>E3>E2 potency, linking the major AD risk gene to APP expression.

    Evidence ES-cell-derived human neurons co-cultured with glia, kinase inhibitors, reporter assays, and in vivo mouse validation

    PMID:28111074

    Open questions at the time
    • ApoE receptor initiating the cascade not pinpointed
    • Contribution relative to ApoE effects on Aβ clearance not addressed
  29. 2017 Medium

    Showed AICD transcriptionally upregulates JNK3 to promote axotomy-induced retinal ganglion cell death, extending AICD's neuronal death program to a defined locus.

    Evidence Optic nerve axotomy, ChIP and luciferase at JNK3 locus, APP knockout, and γ-secretase inhibitor with RGC survival counts

    PMID:29238071

    Open questions at the time
    • Whether JNK3 induction requires Fe65 not addressed
    • Relevance to Aβ-driven degeneration unclear
  30. 2019 High

    Identified APP-βCTF (C99) rather than Aβ as the driver of lysosomal dysfunction in Down syndrome by alkalinizing lysosomes and inactivating cathepsin D.

    Evidence DS fibroblasts and Ts2 neurons, direct lysosomal pH measurement, APP siRNA, BACE1 inhibition, and in vivo Bace1 deletion

    PMID:31043483

    Open questions at the time
    • Mechanism by which C99 raises lysosomal pH undefined
    • Generalization beyond DS/trisomy context not established
  31. 2020 Medium

    Showed statins reduce BACE1 processing by enhancing cholesterol-binding-dependent APP dimerization and reducing APP-BACE1 proximity, linking lipid pharmacology to processing geometry.

    Evidence iPSC-derived neurons, BiFC dimerization, sAPPβ ELISA, and APP cholesterol-binding mutants

    PMID:33296223

    Open questions at the time
    • Reconciliation with palmitoylation-driven dimer favoring β-cleavage unresolved
    • In vivo amyloid effect of statins not shown here
  32. 2020 Medium

    Demonstrated HTT phosphorylation by Akt drives anterograde axonal transport of APP, controlling presynaptic APP and synapse number in AD models.

    Evidence Microfluidic neuron-on-a-chip live imaging and unphosphorylatable HTT knock-in crossed to APPPS1 with synapse and behavior readouts

    PMID:32452382

    Open questions at the time
    • Motor adaptors linking phospho-HTT to APP cargo not identified
    • Effect on Aβ load vs synapse number not separated
  33. 2021 Medium

    Defined Rab35 as a negative regulator of Aβ that sorts APP and BACE1 out of endosomes via distinct effectors ACAP2 and OCRL, countering stress-induced amyloidogenic trafficking.

    Evidence Rab35 perturbation, effector (OCRL/ACAP2) manipulation, glucocorticoid model, and trafficking/Aβ readouts in neurons

    PMID:34876559

    Open questions at the time
    • Coordination with retromer-dependent sorting unclear
    • Upstream control of Rab35 activity undefined
  34. 2021 Low

    Revealed a non-neuronal immune role: surface APP on glioblastoma binds CD74/CXCR4 and phosphorylates SHP-1 to suppress tumor-associated macrophage phagocytosis.

    Evidence Cell-cell communication analysis, APP-CD74/CXCR4 co-IP, phospho-SHP-1, and phagocytosis assays in vitro and in vivo

    PMID:39111632

    Open questions at the time
    • Single co-IP with limited mechanistic depth
    • Whether full-length APP or a fragment is the ligand unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many converging trafficking adaptors, PTMs, dimerization states, and partner interactions are integrated in a single neuron to set the balance between trophic sAPPα signaling and amyloidogenic Aβ/C99 output remains unresolved.
  • No unified model of processing-pathway choice
  • Receptor(s) for sAPPα trophic signaling unidentified
  • Physiological vs pathological thresholds for AICD transcriptional programs undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005634 nucleus 3 GO:0005768 endosome 3 GO:0005794 Golgi apparatus 3 GO:0005764 lysosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
BACE1BRI2CD74DISC1FE65TAG1TRKAVLDLR

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Neuronal activity modulates formation and secretion of Aβ peptides from APP in hippocampal slice neurons; in turn, Aβ selectively depresses excitatory synaptic transmission in an NMDA receptor-dependent manner, suggesting activity-dependent Aβ production participates in a negative feedback on neuronal hyperactivity. Hippocampal slice electrophysiology with APP overexpression, pharmacological blockade of NMDA receptors Neuron Medium 12670422
2003 ADAM9, ADAM10, and ADAM17 each catalyze alpha-secretase cleavage of APP; dsRNA knockdown of each individually in human glioblastoma A172 cells reduced endogenous alpha-secretase activity, indicating these ADAMs collectively constitute the endogenous alpha-secretase. Overexpression in COS-7 cells measuring constitutive and regulated alpha-secretase activity; dsRNA knockdown in A172 cells Biochemical and biophysical research communications Medium 12535668
2001 APP and FE65 colocalize with actin and Mena in lamellipodia and concentrate with β1-integrin in focal complexes; overexpression of APP accelerates cell migration, and co-expression of FE65 dramatically enhances this effect, likely by regulating APP surface levels. Co-localization by immunofluorescence; MDCK wound-healing migration assay; co-expression studies The Journal of cell biology Medium 11425871
2008 TAG1 acts as an extracellular functional ligand of APP; TAG1-APP interaction triggers γ-secretase-dependent AICD release and Fe65-dependent signaling, negatively modulating neurogenesis. Genetic epistasis in TAG1−/−, APP−/−, and Fe65−/− mice confirmed the TAG1→APP→Fe65 pathway order. Co-immunoprecipitation, genetic epistasis using knockout mice, rescue with AICD or AICD Fe65-binding mutant in neural precursor cells Nature cell biology High 18278038
2019 Lysosomal dysfunction in Down syndrome requires the extra APP gene copy and is specifically mediated by elevated APP-βCTF (C99); APP-βCTF raises lysosomal pH (~0.6 units), inactivating cathepsin D and other hydrolases. BACE1 inhibition or siRNA knockdown of APP reversed these deficits. Primary DS fibroblasts and Ts2 mouse neurons; direct lysosomal pH measurement; siRNA knockdown of APP; BACE1 inhibitor treatment; in vivo Bace1 allele deletion in Ts2 mice The Journal of neuroscience High 31043483
2005 BRI2 physically interacts with APP via their transmembrane domains (APP residues 648–719; BRI2 residues 46–106); this interaction is cis (same membrane) and increases cellular APP levels and β-secretase CTFs while decreasing α-secretase CTFs and Aβ secretion. Co-immunoprecipitation in transfected and non-transfected cells; deletion mutagenesis to map interaction domains; measurement of APP processing products The Journal of biological chemistry Medium 16027166
1998 hnRNP C binds a 29-nt element in the 3'-UTR of APP mRNA and stabilizes it; supplementing a reticulocyte lysate translation system with exogenous hnRNP C stabilized wild-type APP mRNA and increased APP protein synthesis ~6-fold, while mRNAs lacking the 29-nt element were unaffected. In vitro rabbit reticulocyte lysate translation; RNA gel mobility shift assays; mutant APP mRNA lacking 29-nt element Nucleic acids research Medium 9649628
2003 APP-BP1 binds the C-terminal 31 amino acids (C31) of APP and colocalizes with APP in lipid rafts; coexpression of the APP-BP1 domain that binds APP abolishes APP-induced neuronal apoptosis and aberrant DNA synthesis, and a dominant-negative NEDD8-conjugating enzyme hUbc12 similarly blocks neuronal apoptosis caused by APP. Co-immunoprecipitation; lipid raft fractionation; dominant-negative hUbc12 overexpression; neuronal apoptosis assay The Journal of cell biology Medium 14557245
2011 APP knockout reduces dendritic spine density (~35% in culture, ~15% in vivo in 12–15-month mice) and dendritic arborization in hippocampal neurons, and impairs long-term potentiation; addition of sAPPα-conditioned medium partially restores spine density, indicating sAPPα mediates APP's trophic role at synapses. APP knockout mouse; primary hippocampal neuron culture; in vivo spine counting in CA1; LTP electrophysiology; sAPPα rescue experiment Molecular and cellular neurosciences Medium 22884903
2011 APP is phosphorylated at Y682 by TrkA upon NGF stimulation; APP physically interacts with TrkA in a Y682-dependent manner, and APP/Y682 in turn regulates activation of the NGF/TrkA signaling pathway in vivo, the subcellular distribution of TrkA, and neuronal sensitivity to NGF. Co-immunoprecipitation; phosphospecific antibodies; in vivo analysis in Y682 knock-in mice; neurotrophic survival assays The Journal of neuroscience Medium 21849536
2014 HuD RNA-binding protein binds the 3'-UTRs of APP and BACE1 mRNAs and increases their half-lives; HuD-overexpressing mice show elevated APP, BACE1, and Aβ levels in brain, establishing HuD as a post-transcriptional regulator of APP expression. RNA immunoprecipitation (RIP); mRNA half-life measurement; HuD-overexpressing transgenic mice; quantification of APP, BACE1, Aβ levels Cell reports Medium 24857657
2007 Phosphomimicking Tyr687 (Y687E) prevents APP endocytosis and dramatically reduces Aβ production, whereas dephosphomimicking (Y687F) preserves endocytosis and favors β-secretase cleavage, demonstrating that Tyr687 phosphorylation status determines APP subcellular targeting and processing pathway. APP-GFP fusion phosphomutants (Y687E and Y687F); live cell imaging; transferrin co-localization; Aβ ELISA Journal of molecular neuroscience Medium 17873282
2009 PKC-mediated phosphorylation of APP at S655 positively modulates APP secretory traffic; phosphomimicking S655 mutants exhibit enhanced Golgi vesicular exit and increased secretory (alpha-secretase) cleavage to sAPP compared to dephosphomimicking mutants. APP695-GFP S655 phosphomutants; Golgi dynamics imaging; sAPP secretion quantification Molecular and cellular biochemistry Medium 19381782
2006 PAT1a binds APP, APLP1, and APLP2 intracellular domains in vivo and co-localizes with them in trans-Golgi network vesicles/endosomes in primary neurons; PAT1a directly interacts with the basolateral sorting signal of APP/APLPs and its overexpression or RNAi knockdown modulates APP cell-surface levels and processing, altering Aβ secretion. Co-immunoprecipitation in vivo; co-localization in primary neurons; RNAi knockdown and overexpression; cell-surface APP quantification; Aβ ELISA The Journal of biological chemistry Medium 17050537
2011 Retromer deficiency (Vps35 knockdown) increases the ratio of secreted Aβ42:Aβ40 and elevates APP C-terminal fragments in exosomes, indicating that retromer-mediated retrograde transport limits amyloidogenic APP processing in late endosomes. siRNA knockdown of Vps35 in HEK-293/APP695 cells; Aβ ELISA; exosome isolation and Western blotting Neurobiology of disease Low 21515373
2015 AICD binds the Wasf1 (WAVE1) promoter and negatively regulates WAVE1 transcription; WAVE1 interacts and colocalizes with APP in the Golgi apparatus and promotes APP-containing vesicle budding and cell-surface APP levels; reducing WAVE1 decreased Aβ production and restored memory deficits in AD mice. Chromatin immunoprecipitation (AICD at Wasf1 promoter); co-immunoprecipitation (WAVE1–APP); vesicle budding assay; Aβ ELISA; in vivo Wasf1 genetic reduction in AD mouse model; behavioral testing Nature medicine High 26280122
2014 DISC1 interacts directly with APP and regulates its surface expression and internalization; DISC1 knockdown increases cell-surface APP, reduces APP internalization, and shifts processing toward alpha-cleavage (elevated sAPPα/APP-CTFα, decreased Aβ); rescue required wild-type DISC1 but not a DISC1 mutant lacking the APP-binding domain. RNAi knockdown in primary cortical neurons; co-immunoprecipitation; cell-surface biotinylation; Western blot; Aβ ELISA Molecular psychiatry Medium 25224257
2011 APP dimer formation is initiated in the endoplasmic reticulum via intermolecular disulfide bonds between cysteines in the extracellular E1 domain; APP isoforms containing the KPI domain show strongly reduced cis-dimerization; dimers formed in the ER remain stably associated at the cell surface. Organelle-retention APP constructs (KKAA-ER, KKFF-Golgi) in CHO-K1 cells; non-reducing SDS-PAGE; E1 domain deletion mutants; split-GFP; cell aggregation assay Cellular and molecular life sciences Medium 22105709
2015 Synaptotagmins (Syt-1, -2, -9) interact with APP in mouse brains in vivo via the 108-amino-acid linker region between E1 and KPI domains; stable overexpression of Syt-1 or Syt-9 increases APP-CTF, sAPP, and Aβ ~2–3-fold, while Syt-1 knockdown reduces Aβ40/42 and sAPPβ, indicating Syt-1 regulates Aβ generation by modulating BACE1-mediated APP cleavage. Affinity purification-coupled mass spectrometry from mouse brains; co-IP in cells and in vivo; GST pull-down domain mapping; stable OE and lentiviral KD; Aβ ELISA Molecular neurodegeneration Medium 26202512
2016 Palmitoylated APP (palAPP) forms dimers preferentially (~90% vs ~20% of total APP); palAPP dimers are predominantly cis-oriented and favor BACE1-mediated β-cleavage over total APP in lipid-rich detergent-resistant membranes; enzymes DHHC7 and DHHC21 increase both palmitoylation and APP dimerization, and pharmacological inhibition of palmitoylation reduces APP dimerization. FLIM/FRET and co-immunoprecipitation for dimerization; DHHC7/DHHC21 overexpression; palmitoylation inhibitors; in vitro BACE1 activity assay with isolated palAPP vs total APP PloS one Medium 27875558
2014 Multimerization of APP CTFβ (C99) significantly impedes γ-secretase cleavage regardless of substrate sequence; the 3xK-APP monomeric mutant increases long Aβ production without altering initial ε-cleavage, demonstrating that primary sequence determines γ-secretase processivity independently of dimerization. Recombinant WT and 3xK-C100 substrates; isolation of monomeric/dimeric/trimeric forms; in vitro γ-secretase cleavage assay measuring ε-cleavage and Aβ production PloS one High 25350374
2017 ApoE secreted by glia binds ApoE receptors on neurons and activates DLK→MKK7→ERK1/2→cFos/AP-1 signaling, which enhances APP transcription and Aβ production with ApoE4 > ApoE3 > ApoE2 potency; this pathway also regulates APP transcription in mouse brain in vivo. ES-cell-derived human neurons co-cultured with glia; kinase inhibitors; transcription factor reporter assays; in vivo mouse brain validation; isoform-specific ApoE comparisons Cell High 28111074
2022 SIRT2 deacetylates APP at lysines K132 and K134; inhibition or genetic deletion of SIRT2 enhances APP acetylation, promotes non-amyloidogenic processing at the cell surface (increased sAPPα), and ameliorates cognitive impairment in APP/PS1 mice. Acetylation site mapping (K132, K134); SIRT2 knockout and pharmacological inhibition; acetylation-mimic APP mutant expression; primary neuron Aβ42 challenge; APP/PS1 behavioral testing Cell reports Medium 35830807
2014 AICD interacts with FoxO in the cytoplasm, translocates with FoxO into the nucleus under oxidative stress, and acts as a transcriptional co-activator of FoxO to promote transcription of the pro-apoptotic gene Bim, mediating APP-induced cell death in Drosophila and mammalian cells. Drosophila genetic screen; co-immunoprecipitation (AICD-FoxO); nuclear fractionation under oxidative stress; luciferase reporter for FoxO-target Bim; loss-of-function phenotypes Cell death & disease Medium 24832605
2017 AICD upregulates JNK3 expression by interacting with the JNK3 gene locus (shown by chromatin immunoprecipitation and luciferase reporter assay); gamma-secretase inhibitors that block AICD production reduce JNK3 and phospho-JNK expression and protect retinal ganglion cells from axotomy-induced death. Mouse optic nerve axotomy model; microarray + ChIP + luciferase reporter for AICD at JNK3 locus; APP knockout; gamma-secretase inhibitor treatment; RGC survival counts Cell death and differentiation Medium 29238071
2001 Caspase cleavage of APP at its cytosolic tail removes the YENP endocytosis signal, reduces APP internalization, and decreases rather than increases Aβ secretion; masking the caspase site did not affect Aβ levels, and caspase activation by serum withdrawal did not increase Aβ secretion—indicating caspase cleavage of APP is unlikely to directly promote amyloidogenesis. Caspase-site masked APP mutants; serum-withdrawal caspase activation; internalization assays; Aβ ELISA The Journal of biological chemistry Medium 11397796
2020 Statins reduce APP processing by BACE1 by decreasing flAPP–BACE1 interaction and enhancing APP dimerization in a cholesterol-binding-dependent manner; statin-induced changes in APP dimerization and APP-BACE1 proximity require cholesterol binding to APP. iPSC-derived human neurons; bimolecular fluorescence complementation (BiFC) for APP dimerization; sAPPβ ELISA; cholesterol-binding mutants of APP Molecular biology of the cell Medium 33296223
2012 FE65 interacts with VLDLR via its PTB1 domain and forms a trimeric complex with APP and VLDLR; this VLDLR–APP interaction alters trafficking and processing of both proteins, and FE65 presence increases the APP–VLDLR interaction in vitro and in vivo. GST pull-down; co-immunoprecipitation in COS7 cells and brain lysates; co-transfection processing assays Molecular neurodegeneration Low 22429478
2009 p53 represses APP promoter activity via a mechanism involving DNA sequences downstream of the transcription start site (+55/+101); p53 reduces binding of transcription factor Sp1 to this region (shown by gel shift and ChIP), thereby lowering APP expression. Transient transfection with APP promoter deletion constructs; gel mobility shift assays; chromatin immunoprecipitation; dominant-negative p53; DNA-damaging drug camptothecin The Biochemical journal Medium 19049493
2021 APP expressed on GBM tumor cell surfaces inhibits phagocytosis of tumor-associated macrophages (TAMs) by binding to the CD74/CXCR4 receptor complex; APP binding to CD74 promotes SHP-1 phosphorylation, and disruption of the APP-CD74 axis upregulates TAM phagocytosis in vitro and in vivo. Cell-cell communication analysis; co-immunoprecipitation (APP–CD74/CXCR4); phospho-SHP-1 measurement; phagocytosis assay in vitro and in vivo Biochimica et biophysica acta. Molecular basis of disease Low 39111632
2021 Rab35 negatively regulates Aβ production by sorting APP and BACE1 out of the endosomal network via distinct effectors: OCRL mediates BACE1 sorting and ACAP2 mediates APP sorting; Rab35 overexpression prevents amyloidogenic trafficking of APP and BACE1 induced by glucocorticoids. Rab35 overexpression/knockdown in neurons; effector (OCRL, ACAP2) perturbation; Aβ ELISA; APP and BACE1 trafficking assays; glucocorticoid treatment model Cell death & disease Medium 34876559
2020 Huntingtin (HTT), upon phosphorylation by Akt, regulates anterograde axonal transport of APP; expression of unphosphorylatable HTT decreases axonal transport of APP, reduces presynaptic APP levels, and increases synaptic density. In APPPS1 mice, ablating HTT phosphorylation in vivo reduced presynaptic APP and restored synapse number and memory. Microfluidic corticocortical neuronal network-on-a-chip; live imaging of APP transport; unphosphorylatable HTT knock-in mice crossed to APPPS1; synapse density counts; behavioral testing eLife Medium 32452382
2004 In Drosophila, overexpression of APP, APLP1, APLP2, and Drosophila APPL induces Notch gain-of-function phenotypes in peripheral nervous system development; genetic analysis identified Numb as a target and implicated Disabled and Neurotactin, placing APP family members in the Notch signaling pathway during neuronal fate determination. Drosophila transgenics; genetic epistasis; appl mutant analysis; cell fate transformation scoring The EMBO journal Medium 15385958
2000 PKCα mediates PMA-regulated sAPP secretion in human NT2N neurons; long-term PMA treatment causing PKCα downregulation abolished both regulated and constitutive sAPP secretion in NT2N cells, demonstrating that PKCα is the primary isoform coupling PKC activation to alpha-secretase-dependent APP cleavage in neurons. PKC isoform-selective downregulation by prolonged PMA; pharmacological inhibitors (Calphostin C, GF109203X); membrane translocation assays; sAPP ELISA Biochemistry Medium 10858291
2008 APP and BACE1 come into close proximity intracellularly but not at the cell surface in living cells, as shown by TIRET microscopy; altering cholesterol levels modulates this proximity and APP processing by BACE1, likely via changes in membrane fluidity. Time-resolved FRET combined with total internal reflection microscopy (TIRET) in living cells; sAPP secretion upon cholesterol manipulation Biochemical and biophysical research communications Low 18374657

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 APP processing and synaptic function. Neuron 1315 12670422
2012 Trafficking and proteolytic processing of APP. Cold Spring Harbor perspectives in medicine 832 22553493
2011 APP processing in Alzheimer's disease. Molecular brain 726 21214928
2010 An overview of APP processing enzymes and products. Neuromolecular medicine 518 20232515
2017 ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion. Cell 439 28111074
2003 Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochemical and biophysical research communications 233 12535668
2012 Physiological functions of APP family proteins. Cold Spring Harbor perspectives in medicine 223 22355794
2001 The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement. The Journal of cell biology 191 11425871
2008 A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nature cell biology 181 18278038
2013 The role of APP and BACE1 trafficking in APP processing and amyloid-β generation. Alzheimer's research & therapy 177 24103387
2008 MicroRNAs can regulate human APP levels. Molecular neurodegeneration 166 18684319
2003 Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease. The international journal of biochemistry & cell biology 153 12824062
2008 Interactions between APP secretases and inflammatory mediators. Journal of neuroinflammation 144 18564425
2012 Amyloid precursor protein (APP) regulates synaptic structure and function. Molecular and cellular neurosciences 141 22884903
2008 Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease. Biochemical Society transactions 126 19021541
2019 Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99). The Journal of neuroscience : the official journal of the Society for Neuroscience 123 31043483
2011 The roles of amyloid precursor protein (APP) in neurogenesis: Implications to pathogenesis and therapy of Alzheimer disease. Cell adhesion & migration 123 21785276
2007 The APP family of proteins: similarities and differences. Biochemical Society transactions 112 17371289
1998 hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA. Nucleic acids research 105 9649628
2005 BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production. The Journal of biological chemistry 101 16027166
2014 HuD regulates coding and noncoding RNA to induce APP→Aβ processing. Cell reports 98 24857657
2017 APP Function and Lipids: A Bidirectional Link. Frontiers in molecular neuroscience 89 28344547
2016 APP Receptor? To Be or Not To Be. Trends in pharmacological sciences 88 26837733
2015 Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles. The Journal of biological chemistry 84 26296890
2011 Retromer disruption promotes amyloidogenic APP processing. Neurobiology of disease 82 21515373
1995 Amyloid precursor protein (APP) expression in multiple sclerosis lesions. Glia 82 8567065
2011 APP physiological and pathophysiological functions: insights from animal models. Cell research 77 21769132
2003 APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain. The Journal of cell biology 77 14557245
2011 Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells. Experimental brain research 76 21960299
2010 The upside of APP at synapses. CNS neuroscience & therapeutics 75 21199446
2018 Role of Amyloid Precursor Protein (APP) and Its Derivatives in the Biology and Cell Fate Specification of Neural Stem Cells. Molecular neurobiology 74 29383688
2017 APP as a Protective Factor in Acute Neuronal Insults. Frontiers in molecular neuroscience 73 28210211
2002 The beta-amyloid precursor protein (APP) and Alzheimer's disease: does the tail wag the dog? Traffic (Copenhagen, Denmark) 67 12383342
2021 Molecular Characteristics of Amyloid Precursor Protein (APP) and Its Effects in Cancer. International journal of molecular sciences 64 34066808
2010 APP transgenic mice: their use and limitations. Neuromolecular medicine 63 21152995
2003 Protein phosphorylation and APP metabolism. Neurochemical research 63 14570401
2012 Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers. EMBO molecular medicine 60 22514144
2004 Interference of human and Drosophila APP and APP-like proteins with PNS development in Drosophila. The EMBO journal 60 15385958
2017 Ethanol Alters APP Processing and Aggravates Alzheimer-Associated Phenotypes. Molecular neurobiology 58 28799137
2012 Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiology of aging 58 23102935
2008 Activity of gamma-secretase on substrates other than APP. Current topics in medicinal chemistry 58 18220928
2001 The amyloidogenic pathway of amyloid precursor protein (APP) is independent of its cleavage by caspases. The Journal of biological chemistry 58 11397796
2014 FoxO mediates APP-induced AICD-dependent cell death. Cell death & disease 57 24832605
2001 Implication of APP secretases in notch signaling. Journal of molecular neuroscience : MN 57 11816790
2012 Platelets and Alzheimer's disease: Potential of APP as a biomarker. World journal of psychiatry 55 24175176
2001 Identification and characterization of App: an immunogenic autotransporter protein of Neisseria meningitidis. Molecular microbiology 54 11532129
2017 Functional Roles of the Interaction of APP and Lipoprotein Receptors. Frontiers in molecular neuroscience 53 28298885
2011 APP is phosphorylated by TrkA and regulates NGF/TrkA signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 21849536
2008 Impact of cholesterol level upon APP and BACE proximity and APP cleavage. Biochemical and biophysical research communications 51 18374657
2021 ggVolcanoR: A Shiny app for customizable visualization of differential expression datasets. Computational and structural biotechnology journal 50 34745458
2010 The functional neurophysiology of the amyloid precursor protein (APP) processing pathway. Neuropharmacology 50 20167227
2018 The amyloid precursor protein (APP) processing as a biological link between Alzheimer's disease and cancer. Ageing research reviews 49 30500566
2016 AChE and the amyloid precursor protein (APP) - Cross-talk in Alzheimer's disease. Chemico-biological interactions 49 27062894
2022 Inhibition of SIRT2 promotes APP acetylation and ameliorates cognitive impairment in APP/PS1 transgenic mice. Cell reports 47 35830807
2014 DISC1 regulates trafficking and processing of APP and Aβ generation. Molecular psychiatry 47 25224257
2004 Biological roles of APP in the epidermis. European journal of cell biology 45 15679106
2015 Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. European journal of human genetics : EJHG 42 25604855
2007 Tyr687 dependent APP endocytosis and Abeta production. Journal of molecular neuroscience : MN 42 17873282
2017 The Role of APP in Structural Spine Plasticity. Frontiers in molecular neuroscience 41 28539872
2015 APP intracellular domain-WAVE1 pathway reduces amyloid-β production. Nature medicine 41 26280122
2009 S655 phosphorylation enhances APP secretory traffic. Molecular and cellular biochemistry 41 19381782
2005 APP processing and the APP-KPI domain involvement in the amyloid cascade. Neuro-degenerative diseases 41 16909010
2019 β-Amyloid precursor protein (APP) and the human diseases. AIMS neuroscience 40 32341983
2012 Neurologic and motor dysfunctions in APP transgenic mice. Reviews in the neurosciences 40 23089603
2018 Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse. Alzheimer's & dementia (New York, N. Y.) 39 29955650
2010 Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease. Neurobiology of aging 39 21196064
2011 APP dimer formation is initiated in the endoplasmic reticulum and differs between APP isoforms. Cellular and molecular life sciences : CMLS 38 22105709
2008 Functional interactions of APP with the apoE receptor family. Journal of neurochemistry 38 18554321
2017 Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice. CNS & neurological disorders drug targets 36 27401064
2015 Synaptotagmins interact with APP and promote Aβ generation. Molecular neurodegeneration 36 26202512
2020 Activation of Mitochondrial Unfolded Protein Response in SHSY5Y Expressing APP Cells and APP/PS1 Mice. Frontiers in cellular neuroscience 35 31969805
2020 Cholesterol-lowering drugs reduce APP processing to Aβ by inducing APP dimerization. Molecular biology of the cell 33 33296223
2006 PAT1a modulates intracellular transport and processing of amyloid precursor protein (APP), APLP1, and APLP2. The Journal of biological chemistry 33 17050537
2012 FE65 as a link between VLDLR and APP to regulate their trafficking and processing. Molecular neurodegeneration 32 22429478
2009 The tumour suppressor p53 regulates the expression of amyloid precursor protein (APP). The Biochemical journal 32 19049493
2004 APP induces neuronal apoptosis through APP-BP1-mediated downregulation of beta-catenin. Apoptosis : an international journal on programmed cell death 32 15192323
2022 Exosomes Mediate APP Dysregulation via APP-miR-185-5p Axis. Frontiers in cell and developmental biology 31 35223832
2017 APP upregulation contributes to retinal ganglion cell degeneration via JNK3. Cell death and differentiation 30 29238071
2023 Exercise training and BDNF injections alter amyloid precursor protein (APP) processing enzymes and improve cognition. Journal of applied physiology (Bethesda, Md. : 1985) 29 37262102
2012 Good gene, bad gene: new APP variant may be both. Progress in neurobiology 29 22727994
2000 Regulation of amyloid precursor protein (APP) secretion by protein kinase calpha in human ntera 2 neurons (NT2N). Biochemistry 29 10858291
2024 Therapeutic modulation of APP-CD74 axis can activate phagocytosis of TAMs in GBM. Biochimica et biophysica acta. Molecular basis of disease 28 39111632
2016 Palmitoylated APP Forms Dimers, Cleaved by BACE1. PloS one 28 27875558
2014 Independent relationship between amyloid precursor protein (APP) dimerization and γ-secretase processivity. PloS one 28 25350374
2014 UV irradiation accelerates amyloid precursor protein (APP) processing and disrupts APP axonal transport. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 24573290
1998 Monogenetic determinants of Alzheimer's disease: APP mutations. Cellular and molecular life sciences : CMLS 27 9791531
2017 APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins. Frontiers in molecular neuroscience 26 28424586
2014 Fenofibrate reduces amyloidogenic processing of APP in APP/PS1 transgenic mice via PPAR-α/PI3-K pathway. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 26 25447788
2000 Protein kinase C regulation of intracellular and cell surface amyloid precursor protein (APP) cleavage in CHO695 cells. Biochemistry 26 11106509
2004 Amyloid precursor protein (APP) and its derivatives change after cellular energy depletion. An in vitro-study. Journal of neural transmission (Vienna, Austria : 1996) 25 15657641
2021 The Protective A673T Mutation of Amyloid Precursor Protein (APP) in Alzheimer's Disease. Molecular neurobiology 24 33914267
2022 A Class I HDAC Inhibitor Rescues Synaptic Damage and Neuron Loss in APP-Transfected Cells and APP/PS1 Mice through the GRIP1/AMPA Pathway. Molecules (Basel, Switzerland) 23 35807406
2021 Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production. Cell death & disease 23 34876559
2020 Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of huntingtin. eLife 23 32452382
2019 Amyloid Precursor Protein (APP) and GABAergic Neurotransmission. Cells 23 31174368
2019 Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice. Aging 22 31744937
2014 Upregulation of APP, ADAM10 and ADAM17 in the denervated mouse dentate gyrus. PloS one 22 24404197
2011 The role of lipoprotein receptors on the physiological function of APP. Experimental brain research 22 21947084
2008 Regulated proteolysis of APP and ApoE receptors. Molecular neurobiology 22 18415033
2021 Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA. Frontiers in aging 21 35822056

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