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FLASH GENE
Symbol APP contributors: shn - updated : 05-12-2012
HGNC name amyloid beta (A4) precursor protein
HGNC id 620
Corresponding disease
AD1 Alzheimer disease 1, early onset familial
HCHWAD hereditary cerebral hemorrhage with amyloidosis, Dutch type
Location 21q21.3      Physical location : 27.252.861 - 27.543.138
Synonym name
  • cerebral vascular amyloid peptide
  • alzheimer disease amyloid protein
  • protease nexin-II
  • amyloid beta (A4) precursor protein (protease nexin-II, Alzheimer disease)
  • peptidase nexin-II
  • cerebral vascular amyloid peptide
  • Synonym symbol(s) CVAP, PN2, AAA, ABPP, APPI, ABETA, PreA4, CTFgamma
    DNA
    TYPE functioning gene
    STRUCTURE 290.28 kb     18 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure 22 exons with the alternative
    MAPPING cloned Y linked Y status confirmed
    Map cen - D21S1907 - D21S265 - APP - D21S1896 - D21S1435 - ter
    Physical map
    ZNF299P 21q21.1 zinc finger protein 299 pseudogene LOC391273 21 similar to eukaryotic translation elongation factor 1 alpha 1; CTCL tumor antigen; translation elongation factor 1 alpha 1-like 14; prostate tumor-inducing protein 1; EF1a-like protein; glucocorticoid receptor AF-1 specific elongati TUBAP 21q21.1 tubulin, alpha pseudogene LOC284821 21q21.2 similar to ribosomal protein L13a; 60S ribosomal protein L13a; 23 kD highly basic protein C21orf42 21q21.3 chromosome 21 open reading frame 42 BIC 21q21 chromosome 21 open reading frame 42 MRPL39 21q11.2-q21 mitochondrial ribosomal protein L39 JAM2 21q21.2 junctional adhesion molecule 2 FDXP2 21q21.3 ferredoxin pseudogene 2 ATP5J 21q21.1 ATP synthase, H+ transporting, mitochondrial F0 complex, subunit F6 GABPA 21q21.2-q21.3 GA binding protein transcription factor, alpha subunit 60kDa APP 21q21.2 amyloid beta (A4) precursor protein (protease nexin-II, Alzheimer disease) CYYR1 21q21.2 cysteine and tyrosine-rich 1 ADAMTS1 21q22.1-q22 a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 1 ADAMTS5 21q22.1-q22 a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 5 (aggrecanase-2) GPXP2 21q21.3 glutathione peroxidase pseudogene 2 EIF4A1P 21q21.2 eukaryotic translation initiation factor 4A, isoform 1, pseudogene RPL10P1 21q21.3 ribosomal protein L10 pseudogene 1 C21orf94 21q21.3 chromosome 21 open reading frame 94 C21orf100 21q22.1 chromosome 21 open reading frame 100 C21orf127 21q21.3 chromosome 21 open reading frame 127 HSPDP7 21q22.11 heat shock 60kDa protein 1 (chaperonin) pseudogene 7 LOC391276 21 similar to hypothetical protein ZNF294 21q22-q22.1 zinc finger protein 294
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 splicing 3423 - 695 neurons and non-neuronal cell types -
    17 splicing 3591 - 751 neurons and non-neuronal cell types -
    18 splicing 3648 - 770 neurons and non-neuronal cell types -
    15 splicing 3255 - 639 neurons and non-neuronal cell types -
    17 splicing 3480 - 714 neurons and non-neuronal cell types -
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately
    Digestivemouthtongue  highly
     stomach   moderately
    Endocrinepancreas   moderately
    Reproductivefemale systembreastmammary gland highly
    Urinarykidney   moderately
    Visualeye   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a large extracellular N terminal domain
  • a serum protease inhibitor-like motif, Kunitz type
  • a single transmembrane pass
  • a REXXE ferroxidase consensus motif (its ferroxidase activity of is unique among its protein family and, like ferritin, correlates with the presence of the mRNA IRE motif, which is not present in APLP1 and APLP2)
  • a short cytoplasmic tail, containing a 15 AA juxtamembrane segment with a single tyrosine forming the basolateral sorting signal (see APPBP2)
  • conjugated GlycoP , MetalloP
    mono polymer homomer , heteromer , dimer
    isoforms Precursor of beta-amyloid peptide
    HOMOLOGY
    interspecies ortholog to APP, pan troglodytes
    ortholog to App, Mus musculus
    ortholog to App, Rattus norvegicus
    Homologene
    FAMILY
  • APP family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    text
  • type I integral membrane protein
  • localizes to the nuclear periphery
  • basic FUNCTION
  • undergoing proteolytic cleavages by either alpha, beta or gamma secretases in or near the transmembrane domain
  • to yield several secreted derivatives, including soluble APP(4kDa) beta peptide (A beta) and a related (4 kDa) protein
  • serine protease inhibitor, inhibiting gelatinase A activity
  • playing a significant role in regulating cerebral thrombosis and increases can profoundly enhance cerebral hemorrhage
  • modulating negatively neurogenesis through APBB1 in the CNTN2-APP signalling pathway
  • functions as a kinesin-I membrane receptor, mediating the axonal transport of beta-secretase and presenilin-1 (Kamal 2001)
  • co-localizes with proteins that define the splicing factor compartment (SFC) and may play a role in pre-mRNA splicing (Muresan 2004)
  • has a key role in the pathological process of Alzheimer's disease (AD) and in regulation of cholesterol and sphingomyelin metabolism (Grimm 2005)
  • primary targets of beta-amyloids is suppression of mitochondrial succinate dehydrogenase, and the vulnerability of the brain of beta-amyloids can be explained by its large dependence on mitochondrial energy production (Kaneko 1995)
  • APP and death receptor 6 (DR6, also known as TNFRSF21) activate a widespread caspase-dependent of a neuronal self-destruction pathway program (Nikolaev 2009)
  • plays an important role in preventing iron-mediated oxidative stress through separate domains: an HO-inhibitory domain that prevents the release of Fe2+ from heme and, here, a separate ferroxidase domain
  • some neurotrophic properties of APP and its fragments could be mediated by iron regulation
  • capable of forming a homodimer through its extracellular domain as well as transmembrane GXXXG motifs
  • CELLULAR PROCESS cell life, cell death/apoptosis
    nucleotide, RNA splicing
    PHYSIOLOGICAL PROCESS development
    text neurogenesis
    PATHWAY
    metabolism lipid/lipoprotein
    signaling
    a component
  • complexing with AABP1 and histone acetyltransferase (Tip60)
  • APP/APBB1/LRP1 complex is an important mediator of APP processing and affects beta-amyloid peptide production
  • modulation of APP dimerization state could be one of mechanisms, which links synaptic contact and Abeta production
  • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • copper Cu2+ (reducing)
  • protein
  • gamma secretase putatively (PSEN1 and PSEN2) to cleavage of APP in Abeta 42 with deposition in brain (fibrillar myeloid plaques to cause neurodegeneration)
  • APBB1, via its C-ter region (LRP2 interacts with APP and APBB1 in neurons
  • sortilin-related receptor, L(DLR class) A repeats-containing (SORL1)
  • APP and APLP bind to heme oxygenase (HO) and inhibit HO activity
  • amyloid beta (A4) precursor protein-binding, family B, member 1 (Fe65)
  • forms a multimeric complex with the nuclear adaptor protein Fe65 and the histone acetyltransferase Tip60
  • amyloid beta (A4) precursor protein-binding, family A, member 1 (APBA1)
  • amyloid beta (A4) precursor protein-binding, family A, member 2 (ABPA2)
  • amyloid beta (A4) precursor protein-binding, family A, member 3 (APBA3)
  • amyloid beta (A4) precursor protein-binding, family B, member 2 (APBB2)
  • amyloid beta (A4) precursor protein-binding, family B, member 3 (APBB3)
  • acetylcholinesterase (AChE)
  • protein interacting with APP tail 1 (PAT1)
  • heparan sulfate proteoglycan 2 (HSPG2)
  • Human bleomycin hydrolase (hBH)
  • Disruption of the disabled-1 gene (Dab1)
  • fibulin 1 (FBLN1)
  • Calreticulin (CALR)
  • glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
  • growth factor receptor-bound protein 2 (GRB2)
  • SHC (Src homology 2 domain containing) transforming protein 1 (SHC1)
  • gelsolin (GSN)
  • intracellular amyloid beta-peptide (A beta) binding protein (ERAB)
  • kinesin-I
  • kininogen 1 (KING1)
  • low density lipoprotein (LDL) receptor-related protein 1B (LRP1B)
  • Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1)
  • 59-kDa APP-binding protein, called APP-BP1
  • nicastrin (NCSTN)
  • Notch inhibitors Numb and Numb-like in mouse brain
  • alpha 1-antichymotrypsin (ACT)
  • synuclein, alpha (non A4 component of amyloid precursor) (SNCA)
  • spondin 1, extracellular matrix protein (SPON1)
  • Transforming growth factor-beta (TGF-beta)
  • TM2 domain containing 1 (TM2D1)
  • mitogen-activated protein kinase 8 interacting protein 1 (MAPK8IP1 aslo known as JIP-1)
  • presenilin 1 (PS1) and presenilin 2 (PS2)
  • human serine protease HtrA2/Omi
  • death receptor 6 (DR6)
  • alpha7 nicotinic acetylcholine receptor (alpha7nAChR)
  • cell death mediator p75(NTR)
  • microtubule-associated protein tau (MAPT)
  • have major interactions with ferroportin to facilitate iron export from certain cells including neurons
  • GAS1 negatively regulated APP intracellular trafficking
  • GULP1-APP interaction is mediated by the NPTY motif of APP and the GULP1 PTB (phosphotyrosine-binding) domain (
  • CDH2 expression facilitates cis-dimerization of APP (
  • interaction between APP and neuroligin-1 (NLGN1), increasing the formation of APP oligomers, and suggesting that this interaction could triggers the targeting of APP oligomer to the postsynaptic regions of excitatory synapses
  • mechanistic link between APOE-regulated cholesterol homeostasis and APP degradation
  • APP endocytic trafficking to lysosomes for degradation is a major APP clearance pathway that is differentially regulated by APOE isoforms
  • APBB1 might have signalling properties together with APP and LRP1
  • APOE influences soluble APP metabolism not through direct binding to soluble APP in solution but through its actions with other interacting receptors/transporters and cell surfaces
  • cell & other
    REGULATION
    induced by cellular uptake and degradation by LRP1
    inhibited by entactin
    Zn2+ in Alzheimer disease tissue
    Other cleaved at the cell surface and released as a soluble APP
    PS1 that regulates the gamma-secretase proteolysis of the amyloid precursor protein (APP)
    prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production
    JIP1b can directly modulate APP metabolism by interacting with the APP cytoplasmic domain
    ASSOCIATED DISORDERS
    corresponding disease(s) AD1 , HCHWAD
    related resource Alzheimer Disease Mutation Database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in cerebral hemorrhage due to congophilic amyloid angiopathy (CAA) with periventricular and subcortical white matter lesions at young age
    constitutional     --low  
    in autism with duplicated UBE3A
    constitutional       loss of function
    inhibition of APP ferroxidase activity may contribute to neuronal iron accumulation in Alzheimer cortex, and elevated brain iron is a complication of aging
    Susceptibility
  • to schizophrenia
  • to Alzheimer disease
  • Variant & Polymorphism other
  • mutation APP692
  • APP-promoter mutations that significantly increase APP expression levels are associated with AD
  • association between rs463946 (-3102 G/C) and AD
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativealzheimer
    postmenopausal estrogen (17beta-estradiol) replacement therapy may prevent or delay the onset of AD
    ANIMAL & CELL MODELS
  • transgenic mouse models expressing human Alzheimer's A beta peptide exhibit brain regions severely affected in Alzheimer's disease resulting in extensive neuronal degeneration (LaFerla 1995)
  • double mutant (tau/APP) mice exhibited neurofibrillary tangle pathology substantially enhanced in the limbic system and olfactory cortex (Lewis 2001)
  • co-expression of both mutant transgenes presenilin 1 and APP results in acceleration of amyloid accumulation and associative learning deficits (Dineley 2002)
  • expression of human Abeta42 peptide in the Drosophila brain led to the formation of diffused amyloid deposits, age-dependent learning defects, and extensive neurodegeneration and Abeta40 caused only age-dependent learning defects (Iijima 2004)
  • FVB/N mice overexpressing human APP695 develop a central nervous system disorder and die prematurely, precluding development of Abeta peptide amyloid plaques whereas 129S6 mice are resistant to the lethal effects of APP overexpression (Krezowski 2004)
  • gene expression analysis revealed that the genes related to mitochondrial energy metabolism and apoptosis were up-regulated in 2-month-old Tg2576 mouse AD model and that the same genes were up-regulated at 5 and 18 months of age suggesting that mitochondrial energy metabolism is impaired by the expression of mutant APP and/or Abeta, and that the up-regulation of mitochondrial genes is a compensatory response (Reddy 2004)
  • estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen, early-onset and increased beta amyloid peptide (Abeta) deposition and increased Abeta production (Yue 2005)
  • memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly suggesting that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease (Lesné 2006)
  • Lack of NO synthase 2 in the amyloid precursor protein Swedish mutant mouse increased insoluble beta-amyloid peptide levels, neuronal degeneration, caspase-3 activation, and tau cleavage (Colton 2006)
  • Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely. Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation (El Khoury 2007)