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Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)

PDB rendering based on 1aap.
Available structures
1aap, 1amb, 1amc, 1aml, 1ba4, 1ba6, 1brc, 1ca0, 1iyt, 1mwp, 1owt, 1rw6, 1taw, 1tkn, 1z0q, 1zjd, 2beg, 2fjz, 2fk1, 2fk2, 2fk3, 2fkl, 2fma, 2g47
External IDs OMIM104760 MGI88059 HomoloGene56379 GeneCards: APP Gene
RNA expression pattern
PBB GE APP 200602 at.png
PBB GE APP 211277 x at.png
PBB GE APP 214953 s at.png
More reference expression data
Species Human Mouse
Entrez 351 11820
Ensembl ENSG00000142192 ENSMUSG00000022892
UniProt P05067 Q8BPC7
RefSeq (mRNA) NM_000484 NM_007471
RefSeq (protein) NP_000475 NP_031497
Location (UCSC) Chr 21:
26.17 - 26.47 Mb
Chr 16:
84.84 - 85.06 Mb
PubMed search [1] [2]
The metal-binding domain of APP with a bound copper ion. The side chains of the two histidine and one tyrosine residues that play a role in metal coordination are shown in the Cu(I) bound, Cu(II) bound, and unbound conformations, which differ by only small changes in orientation.
The extracellular E2 domain, a dimeric coiled coil and one of the most highly-conserved regions of the protein from Drosophila to humans. This domain, which resembles the structure of spectrin, is thought to bind heparan sulfate proteoglycans.[1]

Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation[2] and neural plasticity.[3] APP is best known and most commonly studied as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a 39- to 42-amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.



In humans, the gene for APP is located on chromosome 21 and contains at least 18 exons in 240 kilobases.[4][5] Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 365 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease.[6] Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals.[7] The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state biological functions.[7]

Mutations in critical regions of Amyloid Precursor Protein, including the region that generates amyloid beta, are known to cause familial susceptibility to Alzheimer's disease.[8][9][10] For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.[11]


A number of distinct, largely independently-folding structural domains have been identified in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains; E1 contains several subdomains including a growth factor-like domain (GFLD), a metal-binding motif, and a serine protease inhibitor domain that is absent from the isoform differentially expressed in the brain.[12] The E2 domain contains a coiled coil dimerization motif and may bind proteoglycans in the extracellular matrix.[1] The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, including the copper-binding as well as a zinc-binding domain in multiple configurations and ion-binding states[13] and the E2 dimerization domain.[1]

Post-translational processing

APP undergoes extensive post-translational modification including glycosylation, phosphorylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments.[14] It is commonly cleaved by proteases in the secretase family; alpha secretase and beta secretase both remove nearly the entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with apoptosis.[7] Cleavage by gamma secretase within the membrane-spanning domain generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but include presenilin, whose gene has been identified as a major genetic risk factor for Alzheimer's.[15]

The amyloidogenic processing of APP has been linked to its presence in lipid rafts. When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase.[16] Gamma secretase activity has also been associated with lipid rafts.[17] The role of cholesterol in lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and apolipoprotein E genotype are major risk factors for Alzheimer's disease.[18]

Biological function

Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. The most-substantiated role for APP is in synaptic formation and repair;[2] its expression is upregulated during neuronal differentiation and after neural injury. Roles in cell signaling, long-term potentiation, and cell adhesion have been proposed and supported by as-yet limited research.[7] In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.[19] APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.[20] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.[21] The logical inference is that because Aβ accumulates excessively in Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques.[22] The data indicate that this deficit in APP results from a decline in production rather than an increase in catalysis. Loss of a neuron's APP may effect physiological deficits that contribute to dementia. Recently amyloid precursor protein (APP) origin was demonstrated with arhtiritogenic animals. The source noted is breakdown of immune complexes, where the amyloid aggregates are left degraded and binds together to form coil like feature and does not carried to circulation. Finally it induce secondary inflammation which may cause local damage.[23]


Amyloid precursor protein has been shown to interact with APBA3,[24][25] CLSTN1,[26][27] APPBP1,[28] Gelsolin,[29] BCAP31,[30] Caveolin 1,[31] FBLN1,[32] Collagen, type XXV, alpha 1,[33] APBB1,[34][35][36][37][38] APBA2,[24][27][39] APBA1,[24][34] APPBP2,[40] HSD17B10,[41] BLMH[42] and SHC1.[43]

One groups of scientists reports that APP interacts with reelin, a protein implicated in a number of brain disorders, including Alzheimer's disease.[44]


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  44. ^ Hoe HS, Lee KJ, Carney RS, Lee J, Markova A, Lee JY, Howell BW, Hyman BT, Pak DT, Bu G, Rebeck GW (June 2009). "Interaction of reelin with amyloid precursor protein promotes neurite outgrowth". J. Neurosci. 29 (23): 7459–73. doi:10.1523/JNEUROSCI.4872-08.2009. PMID 19515914. Lay summary – Alzheimer Research Forum.  

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