Affinage

APP

Amyloid-beta precursor protein · UniProt P05067

Round 2 corrected
Length
770 aa
Mass
86.9 kDa
Annotated
2026-04-28
130 papers in source corpus 50 papers cited in narrative 49 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APP is a type I transmembrane glycoprotein that functions as a cell-surface receptor and adhesion molecule whose sequential proteolytic processing by α-secretase (ADAM10/17), β-secretase (BACE1), and γ-secretase generates biologically active fragments—neuroprotective sAPPα, the APP intracellular domain (AICD), and amyloid-β (Aβ) peptides—with the balance between pathways governed by endocytic trafficking via Mint adaptors, retromer/VPS35 recycling, Rab35-directed endosomal sorting, cholesterol-dependent APP dimerization, and post-translational modifications including phosphorylation (Thr668, Tyr682, Ser655) and SIRT2-mediated deacetylation at K132/K134 (PMID:10531052, PMID:22711829, PMID:24742670, PMID:34876559, PMID:35830807). sAPPα promotes dendritic spine maintenance and synaptic plasticity, while Aβ oligomers potently inhibit hippocampal LTP and enhance LTD, and the β-CTF (C99) fragment—independent of Aβ—drives early endosome enlargement and lysosomal de-acidification that impair organelle function in familial Alzheimer's disease and Down syndrome neurons (PMID:22884903, PMID:18568035, PMID:31416668, PMID:31043483). Missense mutations in APP—including the Swedish (K670N/M671L), Dutch (E693Q), London (V717I), and protective Icelandic (A673T) variants—directly cause or modulate risk for familial Alzheimer's disease and hereditary cerebral amyloid angiopathy by altering secretase cleavage efficiencies (PMID:1671712, PMID:2111584, PMID:1302033, PMID:22801501). Beyond the nervous system, APP engages extracellular ligands (TAG1, ApoE, Synaptotagmins, GABAB receptors, CD74) to regulate neurogenesis, GABAergic signaling, axonal transport, and immune-evasive phagocytosis suppression in glioblastoma (PMID:18278038, PMID:28111074, PMID:31174368, PMID:39111632).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1985 High

    Identification of the ~4 kDa Aβ peptide as the biochemical subunit of amyloid plaques established the molecular target for Alzheimer's disease research and defined the product whose precursor would become APP.

    Evidence Purification and NH2-terminal sequencing of amyloid core protein from AD and Down syndrome brains

    PMID:3159021

    Open questions at the time
    • Precursor protein unknown at this stage
    • No information on how Aβ is generated
  2. 1987 High

    Cloning of the full-length APP cDNA revealed it encodes a type I transmembrane glycoprotein with Aβ spanning the ectodomain–transmembrane junction, and mapped the gene to chromosome 21, explaining gene-dosage effects in Down syndrome.

    Evidence cDNA cloning, sequencing, structural prediction, Northern blot, and chromosomal localization

    PMID:2881207 PMID:2949367 PMID:3810169

    Open questions at the time
    • Proteolytic enzymes generating Aβ unknown
    • Normal physiological function of APP undefined
  3. 1991 High

    Discovery that missense mutations in APP (V717I London, E693Q Dutch, K670N/M671L Swedish) segregate with familial AD and hereditary cerebral amyloid angiopathy proved APP is a causal disease gene and linked specific cleavage-site mutations to pathogenic processing.

    Evidence Genetic co-segregation analysis in FAD kindreds and cDNA sequencing of affected patients

    PMID:1302033 PMID:1671712 PMID:2111584

    Open questions at the time
    • Identity of β-secretase and γ-secretase still unknown
    • Mechanism by which mutations alter processing not yet biochemically defined
  4. 1999 High

    Identification of BACE1 as the β-secretase resolved a decade-long search for the enzyme initiating amyloidogenic APP processing, enabling mechanistic dissection of the pathway.

    Evidence Expression cloning, antisense knockdown, and purified enzyme cleavage assay with APP-derived substrates

    PMID:10531052

    Open questions at the time
    • γ-secretase composition not yet fully defined
    • Regulation of BACE1 access to APP in trafficking compartments unclear
  5. 2002 High

    Demonstration that naturally secreted Aβ oligomers—not monomers or fibrils—potently inhibit hippocampal LTP in vivo, and that patient-derived Aβ dimers impair synaptic plasticity and spine density, established the synaptotoxic species and refocused the amyloid hypothesis on soluble oligomers.

    Evidence In vivo hippocampal LTP with immunodepletion; extraction of dimers from human AD cortex with LTP/LTD electrophysiology and spine imaging

    PMID:11932745 PMID:18568035

    Open questions at the time
    • Precise receptor(s) for Aβ oligomers at synapses debated
    • Relative contribution of different oligomer sizes in vivo unresolved
  6. 2003 High

    Identification of ADAM9/10/17 as α-secretases that cleave APP within the Aβ domain, and the finding that neuronal activity modulates APP processing and Aβ release to depress excitatory transmission, placed APP processing within a physiological activity-dependent feedback loop.

    Evidence dsRNA knockdown of ADAMs in cell lines; hippocampal slice electrophysiology with APP overexpression and NMDA-R blockade

    PMID:12535668 PMID:12670422

    Open questions at the time
    • Relative contributions of each ADAM in vivo unresolved
    • Downstream signaling mediating Aβ-induced synaptic depression incompletely mapped
  7. 2008 High

    Discovery that TAG1 (contactin-2) acts as an extracellular APP ligand triggering γ-secretase-dependent AICD release and Fe65-mediated transcription to negatively regulate neurogenesis established APP as a bona fide signaling receptor with developmental functions beyond Aβ production.

    Evidence Genetic epistasis in TAG1−/−, APP−/−, Fe65−/− mice with AICD rescue experiments and neurogenesis assays

    PMID:18278038

    Open questions at the time
    • Full repertoire of extracellular APP ligands and downstream transcriptional targets of AICD incomplete
    • Signaling specificity versus APLP1/APLP2 undetermined
  8. 2011 Medium

    Convergent studies on APP trafficking showed that retromer (VPS35)-mediated retrograde transport from endosomes to the TGN controls amyloidogenic processing; APP dimerizes via E1 domain disulfide bonds in the ER; and phosphorylation at Y682 by TrkA and Y687 regulates APP endocytosis and secretase access, defining post-translational and trafficking control of the amyloidogenic/non-amyloidogenic balance.

    Evidence VPS35 siRNA with Aβ ELISA; organelle-retention constructs with non-reducing SDS-PAGE; phosphomimetic/dephosphomimetic mutants with trafficking assays; TrkA co-IP in APP KO neurons

    PMID:17873282 PMID:21515373 PMID:21849536 PMID:22105709

    Open questions at the time
    • Structural basis of retromer–APP interaction unknown
    • How phosphorylation marks are integrated to set net APP trafficking fate in vivo unclear
  9. 2012 High

    APP knockout mice revealed that sAPPα is the APP fragment responsible for maintaining dendritic spine density, apical dendrite length, and LTP, while the protective Icelandic A673T variant demonstrated that reducing β-secretase cleavage by ~40% is sufficient to protect against AD and cognitive decline across a lifetime.

    Evidence APP−/− spine quantification with sAPPα rescue; Icelandic whole-genome sequencing with in vitro Aβ production assay

    PMID:22801501 PMID:22884903

    Open questions at the time
    • Receptor mediating sAPPα trophic effects not identified
    • Whether A673T-like protection can be recapitulated therapeutically untested
  10. 2014 High

    Mint (X11) adaptors were shown to be required for activity-dependent APP endocytosis and co-internalization with presenilin-1, linking synaptic activity to the spatial compartmentalization of amyloidogenic processing.

    Evidence Mint KO neuronal cultures with glutamate stimulation, APP trafficking assays, Aβ ELISA, PS1 co-localization

    PMID:24742670

    Open questions at the time
    • Mint isoform-specific contributions in vivo uncertain
    • Mechanism coupling glutamate receptor activation to Mint–APP endocytosis not fully resolved
  11. 2017 High

    ApoE-driven transcriptional upregulation of APP via DLK→MKK7→ERK1/2→cFos/AP-1 explained the isoform-dependent effect of ApoE4 > ApoE3 > ApoE2 on Aβ burden, adding a transcriptional layer to the known post-translational regulation of APP processing.

    Evidence Human ES-derived neurons, systematic siRNA of pathway components, reporter assays, in vivo mouse validation

    PMID:28111074

    Open questions at the time
    • Whether this pathway operates in all neuronal subtypes unknown
    • Interaction with other APP transcriptional regulators (Sp1, p53) not integrated
  12. 2019 High

    Isogenic iPSC and Down syndrome studies converged to show that β-CTF (C99)—not Aβ—is the primary driver of early endosome enlargement and lysosomal de-acidification in fAD and trisomy 21, repositioning C99 accumulation as a proximal pathogenic event upstream of lysosomal failure.

    Evidence CRISPR isogenic iPSC lines with BACE inhibitor rescue; DS fibroblasts and Ts2 mouse neurons with lysosomal pH measurement and Bace1 heterozygous deletion in vivo

    PMID:31043483 PMID:31416668

    Open questions at the time
    • How C99 mechanistically impairs v-ATPase to raise lysosomal pH not defined
    • Relative contributions of C99 versus Aβ in late-stage sporadic AD unclear
  13. 2022 High

    SIRT2-mediated deacetylation of APP at K132/K134 was identified as a post-translational switch favoring amyloidogenic processing; genetic deletion or pharmacological inhibition of SIRT2 enhanced APP acetylation, shifted processing to the non-amyloidogenic pathway, and rescued cognition in APP/PS1 mice.

    Evidence SIRT2 KO × APP/PS1 cross, acetylation-mimic APP mutants, sAPPα ELISA, behavioral testing, primary neuron toxicity assay

    PMID:35830807

    Open questions at the time
    • Acetyltransferase responsible for K132/K134 acetylation not identified
    • How acetylation alters APP conformation or secretase accessibility structurally undefined
  14. 2024 Medium

    APP was found to function as a 'don't-eat-me' signal on glioblastoma cells by engaging CD74/CXCR4 on tumor-associated macrophages and activating SHP-1, extending APP's receptor-like functions to immune evasion beyond the nervous system.

    Evidence Co-immunoprecipitation of APP–CD74, phagocytosis assays in vitro and in vivo mouse xenograft

    PMID:39111632

    Open questions at the time
    • Which APP fragment (full-length vs. sAPP) mediates immune evasion not resolved
    • Generalizability to other tumor types untested
    • Physiological role of APP–CD74 interaction in non-neoplastic tissue unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural mechanism by which C99 impairs lysosomal v-ATPase, the identity of the principal sAPPα trophic receptor, how multiple transcriptional (Sp1/AP-1/p53) and post-translational (phosphorylation/acetylation/dimerization/cholesterol) inputs are integrated to set the amyloidogenic–non-amyloidogenic balance in individual neurons, and the full physiological ligand repertoire and signaling output of full-length APP.
  • No high-resolution structure of APP in complex with its secretases or extracellular ligands
  • sAPPα receptor identity unknown
  • Integrated quantitative model of APP processing regulation absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098631 cell adhesion mediator activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005794 Golgi apparatus 4 GO:0005576 extracellular region 3 GO:0005768 endosome 3 GO:0005783 endoplasmic reticulum 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1643685 Disease 6 R-HSA-112316 Neuronal System 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9609507 Protein localization 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 1
Partners
BACE1CNTN2FE65ITM2BNTRK1SIRT2SYT1VPS35
Complex memberships
γ-secretase substrate complex

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 The amyloid plaque core protein in Alzheimer's disease and Down syndrome was purified and characterized as multimeric aggregates of an ~40-residue (~4 kDa) polypeptide, establishing the biochemical identity of the Aβ peptide as the core subunit of senile plaques and vascular amyloid. Protein purification, amino acid composition, NH2-terminal sequencing, molecular mass determination Proceedings of the National Academy of Sciences of the United States of America High 3159021
1987 APP was cloned and its predicted 695-residue precursor protein shown to contain features characteristic of a glycosylated cell-surface receptor (signal peptide, single transmembrane domain, large ectodomain), with the Aβ peptide residing partly in the transmembrane region; the gene maps to chromosome 21. cDNA cloning and sequencing, structural prediction, chromosomal mapping Nature High 2881207
1987 APP mRNA (3.5 kb) was identified in mammalian brain and human thymus, and the APP gene was mapped to chromosome 21, explaining gene dosage effects in Down syndrome. cDNA library screening, Northern blot, chromosomal localization Science High 2949367 3810169
1991 A missense mutation in the APP gene (Val→Ile near the C-terminus of Aβ, codon 717) co-segregates with familial Alzheimer's disease, establishing APP mutations as a cause of inherited AD. Genetic sequencing, co-segregation analysis in FAD kindred Nature High 1671712
1990 A point mutation (Glu→Gln at position 22 of Aβ) in the APP gene causes hereditary cerebral hemorrhage with amyloidosis (Dutch type), demonstrating that APP mutations directly cause cerebral amyloid angiopathy. cDNA cloning and sequencing of exons encoding the amyloid protein from affected patients Science High 2111584
1992 A double mutation at codons 670/671 of APP (Swedish mutation; Lys-Met→Asn-Leu) co-segregates with early-onset familial AD in two large Swedish families; this mutation is adjacent to the β-secretase cleavage site. Sequencing, co-segregation analysis Nature genetics High 1302033
1992 Two GC-element transcription factor binding sites (elements A and C) in the APP promoter confer transcriptional activity; the proximal element A is a 19 bp GC-rich sequence and element C is a GC-palindrome, identified by 5′ deletion analysis and DNase I footprinting. 5′ deletion analysis, DNase I footprinting, gene transfer/reporter assays Nucleic acids research Medium 1738605
1994 APLP2, an APP family member, is processed through the same unusual secretory/cleavage pathway as APP, but lacks the Aβ domain; widely used APP antibodies cross-react with APLP2, confounding prior APP biochemistry. cDNA cloning, in situ hybridization, immunoprecipitation, pulse-chase metabolic labeling The Journal of biological chemistry High 8300594
1998 hnRNP C binds a 29 nt destabilizing element in the APP mRNA 3′-UTR; occupancy of this element by exogenous hnRNP C stabilizes APP mRNA and enhances its translation ~6-fold in a cell-free translation system. In vitro translation (rabbit reticulocyte lysate), RNA gel mobility shift assay, mRNA stability assay with mutant APP mRNA Nucleic acids research Medium 9649628
1999 BACE (β-site APP-cleaving enzyme) was identified as the β-secretase responsible for cleavage of APP at the known β-secretase positions, generating the N-terminus of Aβ; overexpression increased β-secretase products and antisense suppression reduced them; purified BACE cleaved APP-derived substrates with correct sequence specificity. Expression cloning, overexpression, antisense inhibition, purified enzyme cleavage assay, subcellular localization Science High 10531052
2001 Caspase cleavage of APP at its cytosolic tail removes the YENP endocytosis signal, resulting in reduced APP internalization and decreased Aβ secretion; masking the caspase site or activating caspases did not increase Aβ levels, establishing that caspase cleavage of APP is not a direct contributor to amyloidogenesis. APP-GFP endocytosis assays, caspase-site mutants, serum-withdrawal caspase activation, Aβ ELISA The Journal of biological chemistry Medium 11397796
2002 Naturally secreted oligomers of Aβ derived from APP-overexpressing cells potently inhibit hippocampal LTP in vivo; immunodepletion of all Aβ species abolished the effect; insulin-degrading enzyme (which degrades monomers but not oligomers) did not prevent LTP inhibition, demonstrating that Aβ oligomers (not monomers or fibrils) are the synaptotoxic species. Hippocampal microinjection in vivo, immunodepletion, enzymatic treatment, LTP electrophysiology Nature High 11932745
2003 Neuronal activity modulates APP processing and Aβ secretion in hippocampal 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 to limit neuronal hyperactivity. Hippocampal slice electrophysiology, APP overexpression, pharmacological NMDA-R blockade Neuron High 12670422
2003 ADAM9, ADAM10, and ADAM17 each catalyze the constitutive and regulated α-secretase cleavage of APP (within the Aβ domain, precluding Aβ formation) in COS-7 and human glioblastoma A172 cells; dsRNA knockdown of each individual ADAM reduced endogenous α-secretase activity. Overexpression in COS-7 cells, dsRNA knockdown in A172 cells, APP processing assays Biochemical and biophysical research communications Medium 12535668
2004 APP overexpression (APP695) in neuronal cells substantially decreased AChE mRNA, protein and catalytic activity through a mechanism requiring the E1 region (copper-binding domain) of APP and independent of APP processing or AICD. APP overexpression, siRNA knockdown, RT-PCR, enzymatic activity assays, domain deletion constructs Chemico-biological interactions Medium 27062894
2004 APP induces neuronal apoptosis through APP-BP1-mediated activation of the neddylation pathway, causing downregulation of β-catenin; FAD mutations in APP and presenilins hyperactivate this neddylation pathway. Molecular biology/cellular assays (reviewed mechanistic evidence linking APP→APP-BP1→neddylation→β-catenin depletion→apoptosis) Apoptosis Low 15192323
2004 Full-length APP in the mammalian epidermis facilitates keratinocyte adhesion via interaction with extracellular matrix; the APP C-terminus acts as an adapter for kinesin, mediating centripetal transport of melanosomes; sAPPα released by α-secretase acts as an epidermal growth factor stimulating keratinocyte proliferation, migration, and melanin exocytosis. Hydroxamic acid α-secretase inhibition, cell adhesion assays, melanosome transport studies, proliferation/migration assays European journal of cell biology Medium 15679106
2005 BRI2 interacts with APP via transmembrane domain-containing regions (APP residues 648–719 and BRI2 residues 46–106) in cis on the same cell membrane; BRI2 presence increases cellular APP levels and β-secretase-generated C-terminal fragments while decreasing α-secretase products and total Aβ secretion. Co-immunoprecipitation with deletion mutants, APP processing assays (Western blot, ELISA) The Journal of biological chemistry Medium 16027166
2006 APP forms homodimers and APP/Notch2 heterodimers in living cells; APP homodimer and APP-truncated Notch2 heterodimer complexes localize to plasma membrane, ER, and Golgi, visualized by bimolecular fluorescence complementation (BiFC). Bimolecular fluorescence complementation (BiFC) in living COS-7 cells, flow cytometry, co-immunoprecipitation from embryonic rat brain Journal of neurochemistry Medium 16515557
2007 APP Tyr687 phosphorylation status controls APP targeting and processing: a phosphomimetic Y687E mutant accumulates at the membrane without entering transferrin-positive endosomes and dramatically reduces Aβ production; a dephosphomimetic Y687F mutant undergoes normal endocytosis but is preferentially processed by β-secretase. APP-GFP phosphomutant expression, subcellular fractionation, confocal microscopy, Aβ ELISA Journal of molecular neuroscience Medium 17873282
2008 TAG1 (contactin-2) is a functional extracellular ligand of APP; TAG1 binding to APP stimulates γ-secretase-dependent release of the APP intracellular domain (AICD) and Fe65-dependent transcriptional activity; this TAG1-APP-Fe65 pathway negatively regulates neurogenesis in the fetal ventricular zone. Co-localization, genetic epistasis with TAG1−/−, APP−/−, Fe65−/− mice, rescue with AICD/Fe65-binding mutants, neural precursor cell neurogenesis assays Nature cell biology High 18278038
2008 miRNAs hsa-mir-106a and hsa-mir-520c bind predicted target sequences in the APP mRNA 3′-UTR and negatively regulate APP translation; overexpression of these miRNAs in human cell lines significantly reduces APP protein levels. Luciferase reporter assays with APP 3′-UTR, miRNA overexpression, Western blot for APP protein Molecular neurodegeneration Medium 18684319
2008 Soluble Aβ dimers isolated directly from Alzheimer's disease cortex inhibit hippocampal LTP, enhance LTD, and reduce dendritic spine density in rodent hippocampus; Aβ dimers also impair learned behavior in rats; LTD enhancement requires metabotropic glutamate receptors and spine loss requires NMDA receptors. Extraction of soluble Aβ from human AD cortex, in vivo/ex vivo LTP/LTD electrophysiology, dendritic spine imaging, pharmacological receptor blockade, antibody rescue Nature medicine High 18568035
2009 APP phosphorylation at S655 by PKC is a positive signal for APP secretory traffic: phosphomimicking S655E mutant shows increased Golgi vesicular exit and enhanced secretory cleavage to sAPP, while dephosphomimicking S655A shows reduced secretory processing. APP695-GFP phosphomutant expression, Golgi dynamics analysis, sAPP secretion assay Molecular and cellular biochemistry Medium 19381782
2009 p53 represses APP promoter activity through a mechanism involving reduction of Sp1 binding to a +55/+101 region downstream of the transcription start site, without direct p53-DNA binding to this region; Sp1 binding was confirmed by EMSA and chromatin immunoprecipitation. Reporter gene deletion constructs, EMSA, chromatin immunoprecipitation, dominant-negative p53 mutant, pharmacological p53 activation The Biochemical journal Medium 19049493
2011 APP forms disulfide-bonded dimers initiated in the ER via cysteines in the extracellular E1 domain; ER retention and reducing conditions abolish dimers; APP isoforms containing the KPI domain show reduced cis-dimerization compared to APP695, while trans-mediated cell aggregation is isoform-independent. Organelle retention constructs (KKAA/KKFF), non-reducing SDS-PAGE, split-GFP dimerization assay, E1 domain deletion, Drosophila S2 cell aggregation assay Cellular and molecular life sciences Medium 22105709
2011 APP is phosphorylated at Y682 by TrkA; APP interacts with TrkA in a Y682-dependent manner; this interaction is required for proper subcellular distribution of TrkA and sensitization of neurons to NGF, establishing a bidirectional regulatory relationship between APP and the NGF/TrkA signaling pathway in vivo. In vivo phosphorylation assays, co-immunoprecipitation, TrkA localization in APP knock-out neurons, NGF survival assays The Journal of neuroscience High 21849536
2011 Dab1 and APP show a genetic interaction during brain development: overexpression of APP(swe) exacerbates Dab1-hypomorphic neuronal ectopias and cerebellar Purkinje cell misplacement, while APP deficiency ameliorates the cerebellar phenotype, indicating APP constrains Dab1 function during neuronal lamination. Genetic epistasis in transgenic and APP-knockout mice crossed to Dab1 hypomorphs, histological analysis Molecular and cellular neurosciences Medium 18029196
2011 Retromer (VPS35) deficiency increases the Aβ42:Aβ40 ratio and causes accumulation of APP C-terminal fragments and holo-APP in exosomal vesicles, demonstrating that retromer-mediated retrograde trafficking of APP modulates amyloidogenic processing. VPS35 siRNA knockdown in HEK-293 cells, Aβ ELISA, exosome isolation and Western blot Neurobiology of disease Medium 21515373
2011 GULP1 interacts with APP via the NPTY motif of APP and the GULP1 PTB domain; overexpression of GULP1 enhances APP CTF and Aβ generation while knockdown suppresses them; GULP1 co-localizes with APP in neurons. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, confocal co-localization, APP-GAL4 reporter assay, GULP1 overexpression/knockdown with CTF/Aβ quantification The Biochemical journal Medium 21486224
2012 APP traffics from the cell surface via endosomes to the trans-Golgi network (TGN) for Aβ production; retromer (VPS35)-mediated recycling of APP from early endosomes to the TGN is required for efficient Aβ40 production; depletion of Hrs/Tsg101 retains APP in early endosomes and reduces Aβ40, while depletion of CHMP6/VPS4 reroutes APP to TGN and enhances processing. RNAi knockdown of trafficking components, APP trafficking assays, Aβ40 ELISA Proceedings of the National Academy of Sciences High 22711829
2012 APP knock-out mice exhibit ~35% reduction in dendritic spine density in hippocampal neurons (in vitro) and ~15% reduction in vivo at 12–15 months; these deficits are accompanied by reduced LTP and shortened apical dendrites; sAPPα-conditioned medium partially rescues spine density, identifying sAPPα as the APP product responsible for maintaining dendritic integrity. APP−/− mouse model, spine density quantification, LTP electrophysiology, sAPPα rescue experiments Molecular and cellular neurosciences High 22884903
2012 A novel APP mutation K16N (A687N in APP770 numbering) at the α-secretase cleavage site increases Aβ peptide production; Aβ42-K16N itself is non-toxic but forms highly toxic heteromeric oligomers with wild-type Aβ42; Aβ42-K16N inhibits fibril formation of wild-type Aβ42 and is resistant to neprilysin-mediated degradation. APP transfection with mutant constructs, Aβ ELISA, cell toxicity assay, fibril formation assays, neprilysin cleavage assay EMBO molecular medicine Medium 22514144
2012 A protective APP variant A673T (adjacent to the Swedish mutation at the β-secretase site) reduces amyloidogenic peptide formation by ~40% in vitro and protects against Alzheimer's disease and age-related cognitive decline in Icelanders. Whole-genome sequencing, genetic association, in vitro Aβ production assay with A673T-APP expressing cells Nature High 22801501
2014 APP CTFβ dimers are poor γ-secretase substrates compared to monomers; monomeric 3xK-C100 mutant (with sequence changes at the ectodomain–TMD border) increases long Aβ production without altering initial ε-cleavage, demonstrating that γ-secretase processivity is determined by substrate primary sequence independent of dimerization state. Recombinant C100 substrate isolation (monomer/dimer/trimer fractions), in vitro γ-secretase cleavage assay, Aβ species quantification by mass spectrometry PloS one Medium 25350374
2014 Mint (X11) adaptor proteins are required for activity-dependent APP endocytosis and Aβ generation in neurons; neuronal activation by glutamate increases APP endocytosis and surface reinsertion, while Mint knockout blocks both; wild-type Mint1 rescues APP internalization; Mint PDZ domains mediate activity-dependent co-endocytosis of APP with presenilin-1 (PS1). Mint KO neuronal cultures, glutamate/TTX stimulation, APP trafficking assays (biotinylation, endocytosis), Aβ ELISA, PS1 co-localization The Journal of biological chemistry High 24742670
2014 DISC1 interacts with APP and regulates its proteolytic processing and cell-surface expression: DISC1 knockdown increases APP-CTFα and sAPPα, decreases Aβ42/40, and increases APP at the cell surface with reduced internalization; these effects require the DISC1-APP interaction domain. RNAi knockdown, DISC1 KO mouse model, co-immunoprecipitation, APP surface biotinylation, Aβ/CTF quantification, rescue with WT vs. mutant DISC1 Molecular psychiatry Medium 25224257
2015 Synaptotagmin-1 (Syt-1) and Syt-9 interact with APP via a 108-amino acid linker region between the E1 and KPI domains; overexpression of Syt-1 or Syt-9 increases APP-CTF, sAPP, and secreted Aβ 2–3-fold; knockdown of endogenous Syt-1 reduces Aβ40/42 and CTF levels in PC12 cells and primary neurons; Syt-1 regulates Aβ generation by modulating BACE1-mediated APP cleavage. Affinity purification/mass spectrometry from mouse brain, GST pulldown, co-IP in cells and brain, stable OE and KD, Aβ ELISA, lentiviral KD in primary neurons Molecular neurodegeneration High 26202512
2016 NGF controls APP phosphorylation at Thr668 by downregulating JNK(p54) activity through the ShcC signaling adaptor; TrkA fails to interact with APP phosphorylated at T668; NGF promotes TrkA binding to APP, APP trafficking to the Golgi (where BACE interaction is reduced), and consequently decreases sAPPβ, CTFβ, and Aβ42. Primary septal neuron and brain slice cultures, kinase activity assays, co-IP of TrkA-APP, ShcC KO mice, hippocampal samples from AD patients, Aβ ELISA Aging cell High 27076121
2017 ApoE secreted by glia stimulates APP transcription and Aβ production in neurons via ApoE receptor→DLK→MKK7→ERK1/2→cFos phosphorylation→AP-1-mediated APP transcription; ApoE4 > ApoE3 > ApoE2 in potency; this pathway also operates in mouse brain in vivo. ES cell-derived human neurons, siRNA knockdown of pathway components, reporter assays, in vivo mouse experiments, Aβ ELISA Cell High 28111074
2018 miR-346 targets the APP mRNA 5′-UTR (overlapping with the iron-responsive element and the IL-1 acute box) to upregulate APP translation and Aβ production; this effect is partially dependent on Argonaute 2 and requires iron chelation in primary human brain cultures, identifying a novel 5′-UTR miRNA-mediated translational activation mechanism for APP. Reporter assays with APP 5′-UTR, miR-346 overexpression, Ago2 knockdown, primary human brain cultures, iron chelation Molecular psychiatry Medium 30470799
2019 APP β-CTF (C99) — not Aβ — mediates endosomal dysfunction in familial AD iPSC-derived neurons; all fAD mutations (APP and PSEN1) produced convergent early endosome enlargement correlating with β-CTF accumulation; BACE1 inhibition rescued endosomal phenotypes, demonstrating C99 as the pathogenic APP fragment upstream of endosomal pathology. CRISPR/Cas9 isogenic iPSC lines, transcriptomics/translatomics, Rab5+ endosome imaging, pharmacological BACE inhibition, Aβ and β-CTF quantification Neuron High 31416668
2019 APP β-CTF (C99), at levels produced by a single extra copy of the APP gene in Down syndrome, impairs lysosomal acidification (raising pH by ~0.6 units), inactivating cathepsin D and other lysosomal hydrolases; BACE1 inhibition or partial deletion of Bace1 in Ts2 mice reversed lysosomal deficits both in vitro and in vivo. DS patient fibroblasts, Ts2 mouse neurons, lysosomal pH measurement (fluorescent probes), cathepsin activity assays, siRNA, BACE inhibitors, Bace1 heterozygous deletion in vivo, acidic nanoparticle rescue The Journal of neuroscience High 31043483
2019 APP directly interacts with KCC2 (potassium-chloride cotransporter) to modulate neuronal chloride homeostasis and GABA reversal potential; APP also binds the sushi domain of GABAB receptor 1a (GABABR1a) and is co-transported with GABAB receptor dimers to the axonal presynaptic membrane, where sAPP can act as a GABABR1a ligand modulating presynaptic vesicle release. Co-immunoprecipitation, co-transport assays, APP overexpression/knockdown, electrophysiological measurement of EGABA Cells Medium 31174368
2020 Huntingtin (HTT) phosphorylated by Akt regulates anterograde axonal transport of APP; expression of unphosphorylatable HTT decreases axonal APP transport, reduces presynaptic APP levels, and increases synaptic density; ablating HTT phosphorylation in APPPS1 mice reduces presynaptic APP, restores synapse number, and improves learning and memory. Microfluidic corticocortical neuronal network-on-a-chip, live imaging of APP transport, HTT phosphomutant knock-in mice crossed to APPPS1, synapse density quantification, behavioral testing eLife Medium 32452382
2020 Statins reduce APP processing to Aβ by promoting APP dimerization and decreasing APP-BACE1 interaction; this effect is dependent on cholesterol binding to APP, suggesting competition between APP dimerization and cholesterol binding regulates BACE1 access to APP. iPSC-derived neurons, bimolecular fluorescence complementation for APP dimerization, APP-BACE1 proximity assay, cholesterol manipulation, Aβ and sAPPβ ELISA Molecular biology of the cell Medium 33296223
2021 Rab35, via its effectors OCRL (for BACE1) and ACAP2 (for APP), sorts APP and BACE1 out of the endosomal network to reduce their interaction and Aβ production; Rab35 overexpression prevents glucocorticoid-induced amyloidogenic APP-BACE1 co-trafficking; Rab35 levels are decreased by stress, glucocorticoids, and aging. Neuronal overexpression/knockdown of Rab35 and effectors, APP/BACE1 co-localization by confocal, Aβ ELISA, glucocorticoid treatment Cell death & disease Medium 34876559
2022 SIRT2 deacetylates APP at lysines K132 and K134; inhibition or genetic deletion of SIRT2 enhances APP acetylation at these residues, promotes non-amyloidogenic processing at the cell surface (increased sAPPα), and ameliorates cognitive impairment in APP/PS1 mice; acetylation-mimic APP mutant protects neurons from Aβ42 toxicity. SIRT2 KO mice crossed to APP/PS1, pharmacological SIRT2 inhibition, acetylation-mimic/deficient APP mutants, sAPPα ELISA, behavioral testing, primary neuron toxicity assay Cell reports High 35830807
2024 APP on the surface of GBM tumor cells inhibits phagocytosis by tumor-associated macrophages (TAMs) through binding to the CD74/CXCR4 receptor complex, promoting phosphorylation of SHP-1; disrupting the APP-CD74 axis upregulates TAM phagocytosis in vitro and in vivo. Cell-cell communication analysis, co-immunoprecipitation, phagocytosis assays in vitro and in vivo mouse xenograft Biochimica et biophysica acta. Molecular basis of disease Medium 39111632

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1987 The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 4057 2881207
1985 Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proceedings of the National Academy of Sciences of the United States of America 3809 3159021
1991 Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 3771 1671712
2002 Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 3567 11932745
2003 Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science (New York, N.Y.) 3365 12702875
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