Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease), also known as APP, is a human gene.
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 and neural plasticity. APP is best known and most commonly studied as the precursor molecule whose proteolysis generates amyloid beta, a 39-42 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. 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. Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals. 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 APP, including the region that generates amyloid beta, are known to cause familial susceptibility to Alzheimer's disease. For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.
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. The E2 domain contains a coiled coil dimerization 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 states and the E2 dimerization domain.
APP undergoes extensive post-translational modification including glycosylation, phosphorylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments. 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. 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 notably include presenilin, whose gene has been identified as a major genetic risk factor for Alzheimer's.
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. Gamma secretase activity has also been associated with lipid rafts. 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.
Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. The most well-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 adhesion have 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.APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss. On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.
- Wang Y, Ha Y. (2006). The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Mol Cell 15(3):343-53. PMID 15304215
- Priller 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
- 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
- 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
- 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
- Zheng H, Koo EH. (2006). The amyloid precursor protein: beyond amyloid. Mol Neurodegener 3;1:5. PMID 16930452
- 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
- 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
- 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
- Kong 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.
- 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
- 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
- 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
- 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
- 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
- Selkoe D, Kopan R. (2003). Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 26:565-597. PMID 12730322
- 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
- 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
- Beyreuther K, Pollwein P, Multhaup G, et al. (1993). Regulation and expression of the Alzheimer's beta/A4 amyloid protein precursor in health, disease, and Down's syndrome.. Ann. N. Y. Acad. Sci. 695: 91-102.
- Straub JE, Guevara J, Huo S, Lee JP (2003). Long time dynamic simulations: exploring the folding pathways of an Alzheimer's amyloid Abeta-peptide.. Acc. Chem. Res. 35 (6): 473-81.
- Annaert W, De Strooper B (2003). A cell biological perspective on Alzheimer's disease.. Annu. Rev. Cell Dev. Biol. 18: 25-51.
- Koo EH (2003). The beta-amyloid precursor protein (APP) and Alzheimer's disease: does the tail wag the dog?. Traffic 3 (11): 763-70.
- Van Nostrand WE, Melchor JP, Romanov G, et al. (2003). Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor.. Ann. N. Y. Acad. Sci. 977: 258-65.
- Ling Y, Morgan K, Kalsheker N (2004). Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease.. Int. J. Biochem. Cell Biol. 35 (11): 1505-35.
- Kerr ML, Small DH (2005). Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development.. J. Neurosci. Res. 80 (2): 151-9.
- Maynard CJ, Bush AI, Masters CL, et al. (2005). Metals and amyloid-beta in Alzheimer's disease.. International journal of experimental pathology 86 (3): 147-59.
- Tickler AK, Wade JD, Separovic F (2005). The role of Abeta peptides in Alzheimer's disease.. Protein Pept. Lett. 12 (6): 513-9.
- Reinhard C, Hébert SS, De Strooper B (2006). The amyloid-beta precursor protein: integrating structure with biological function.. EMBO J. 24 (23): 3996-4006.
- Watson D, Castaño E, Kokjohn TA, et al. (2006). Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease.. Neurol. Res. 27 (8): 869-81.
- Calinisan V, Gravem D, Chen RP, et al. (2006). New insights into potential functions for the protein 4.1 superfamily of proteins in kidney epithelium.. Front. Biosci. 11: 1646-66.
- Vetrivel KS, Thinakaran G (2006). Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments.. Neurology 66 (2 Suppl 1): S69-73.
- Gallo C, Orlassino R, Vineis C (2006). [Recurrent intraparenchimal haemorrhages in a patient with cerebral amyloidotic angiopathy: description of one autopsy case]. Pathologica 98 (1): 44-7.
- Coulson EJ (2006). Does the p75 neurotrophin receptor mediate Abeta-induced toxicity in Alzheimer's disease?. J. Neurochem. 98 (3): 654-60.
- Menéndez-González M, Pérez-Pinera P, Martínez-Rivera M, et al. (2006). APP processing and the APP-KPI domain involvement in the amyloid cascade.. Neuro-degenerative diseases 2 (6): 277-83.
- Neve RL, McPhie DL (2007). Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis.. Biochim. Biophys. Acta 1772 (4): 430-7.
- Chen X, Stern D, Yan SD (2007). Mitochondrial dysfunction and Alzheimer's disease.. Current Alzheimer research 3 (5): 515-20.
- Caltagarone J, Jing Z, Bowser R (2007). Focal adhesions regulate Abeta signaling and cell death in Alzheimer's disease.. Biochim. Biophys. Acta 1772 (4): 438-45.
- Wolfe MS (2007). When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease.. EMBO Rep. 8 (2): 136-40.