- Amyloid precursor protein
Amyloid precursor protein (APP) is an
integral membrane proteinexpressed 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 formationPriller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. (2006). Synapse formation and function is modulated by the amyloid precursor protein. "J Neurosci" 26(27):7212-21. PMID 16822978] and neural plasticity.Turner PR, O'Connor K, Tate WP, Abraham WC. (2003). Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity, and memory. "Prog Neurobiol" 70(1):1-32. PMID 12927332] APP is best known and most commonly studied as the precursor molecule whose proteolysisgenerates amyloid beta(Aβ), a 39- to 42- amino acid peptidewhose amyloidfibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's diseasepatients.
humans, the genefor APP is located on chromosome 21and contains at least 18 exons in 240 kilobases. Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y (1990). Genomic organization of the human amyloid beta-protein precursor gene "Gene" 87:257-263. PMID 2110105] Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, Pearson PL, Price DL, Gearhart JD. (1993). Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice "Nat Genet" 5:22-30. PMID 8220418 ] Several alternative splicingisoforms 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.Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, Frosch MP, Irizarry MC, Hyman BT. (2007). Expression of APP pathway mRNAs and proteins in Alzheimer's disease. "Brain Res" Epub. PMID 17586478 ] Homologous proteins have been identified in other organisms such as " Drosophila" (fruit flies), " C. elegans" (roundworms), and all mammals.Zheng H, Koo EH. (2006). The amyloid precursor protein: beyond amyloid. "Mol Neurodegener" 3;1:5. PMID 16930452] 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.
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.Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. "Nature" 349(6311):704-6. PMID 1671712 ] Murrell J, Farlow M, Ghetti B, Benson MD. (1991). A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. "Science" 254(5028):97-9. PMID 1925564 ] Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, et al. (1991). Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. "Nature" 353(6347):844-6. PMID 1944558] For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ. (1992). Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. "Nature" 360(6405):672-4. PMID 1465129]
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 inhibitordomain that is absent from the isoform differentially expressed in the brain. Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL. (1993). Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. "J Neurosci" 13:3136-3142. PMID 8331390 ] The E2 domain contains a coiled coildimerization motif and may bind proteoglycans in the extracellular matrix. The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, including the copper-binding domain in multiple configurations and ion-binding statesKong GK, Galatis D, Barnham KJ, Polekhina G, Adams JJ, Masters CL, Cappai R, Parker MW, McKinstry WJ. (2005). Crystallization and preliminary crystallographic studies of the copper-binding domain of the amyloid precursor protein of Alzheimer's disease. "Acta Crystallograph" 61(Pt 1):93-5. PMID 16508101. See also 2007 PDB IDs 2FJZ, 2FK2, 2FKL.] and the E2 dimerization domain.
APP undergoes extensive
post-translational modificationincluding glycosylation, phosphorylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments.De Strooper B, Annaert W. (2000). Proteolytic processing and cell biological functions of the amyloid precursor protein. "J Cell Sci" 113 ( Pt 11):1857-70. PMID 10806097 ] It is commonly cleaved by proteases in the secretasefamily; alpha secretaseand beta secretaseboth remove nearly the entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with apoptosis. Cleavage by gamma secretasewithin 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.Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P. (2006). TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. "Nature" 440:1208-1212. PMID 16641999 ]
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.Ehehalt R, Keller P, Haass C, Thiele C, Simons K. (2003). Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. "J Cell Biol" 160(1):113-23. PMID 12515826 ] Gamma secretase activity has also been associated with lipid rafts.Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G. (2004). Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. "J Biol Chem" 279(43):44945-54. PMID 15322084] The role of cholesterolin lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and apolipoprotein E genotypeare major risk factors for Alzheimer's disease.Riddell DR, Christie G, Hussain I, Dingwall C. (2001). Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. "Curr Biol" 11(16):1288-93. PMID 11525745]
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; its expression is upregulated during neuronal differentiation and after neural injury. Roles in
cell signaling, long-term potentiation, and cell adhesionhave been proposed and supported by as-yet limited research. In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch. Selkoe D, Kopan R. (2003). Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. "Annu Rev Neurosci" 26:565-597. PMID 12730322 ] APP knockout miceare viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.Phinney AL, Calhoun ME, Wolfer DP, Lipp HP, Zheng H, Jucker M. (1999). No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice. "Neuroscience" 90(4):1207-16. PMID 10338291 ] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.Matsuyama S, Teraoka R, Mori H, Tomiyama T. (2007). Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice. "Neuroreport" 18(10):1083-7. PMID 17558301 ] 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.cite journal | author = Barger SW, DeWall KM, Liu L, Mrak RE, Griffin WS | title = Relationships between expression of apolipoprotein E and beta-amyloid precursor protein are altered in proximity to Alzheimer beta-amyloid plaques: potential explanations from cell culture studies | journal = J. Neuropathol. Exp. Neurol. | volume = 67 | issue = 8 | pages = 773–83 | year = 2008 | month = August | pmid = 18648325 | doi = 10.1097/NEN.0b013e318180ec47 | url = | issn = ] 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.
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* [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=351 Entrez Gene: APP amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)]
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