Understanding the Brain

Amyloid precursor protein

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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], neural plasticity[3] and iron export.[4] APP is best known and most commonly studied as the precursor molecule whose proteolysis generates beta amyloid (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.[5][6] 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.[7] Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals.[8] 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.[8]

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.[9][10][11] For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.[12]


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, linked by an acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain (GFLD) and a copper-binding domain (CuBD) interacting tightly together.[13] A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain.[14] The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain[15], the copper-binding domain[16], the complete E1 domain[13] and the E2 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.[17] 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.[8] 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.[18]

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.[19] Gamma secretase activity has also been associated with lipid rafts.[20] 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.[21]

Biological function

Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive.

Synaptic formation and repair

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.[8] In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.[22] APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.[23] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.[24] 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.[25] 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 affect physiological deficits that contribute to dementia.

Iron export

A different perspective on Alzheimer's is revealed by a mouse study that has found that APP possesses ferroxidase activity similar to ceruloplasmin, facilitating iron export through interaction with ferroportin; it seems that this activity is blocked by zinc trapped by accumulated Aβ in Alzheimer's.[4]

Hormonal regulation of AβPP expression and processing during embryogenesis and Alzheimer’s disease

The amyloid-β precursor protein (AβPP) and all associated secretases are expressed early in development and plays a key role in the endocrinology of reproduction – with the differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC). The pregnancy hormone human chorionic gonadotropin (hCG) increases AβPP expression [26] and hESC proliferation while progesterone directs AβPP processing towards the non-amyloidogenic pathway which promotes hESC differentiation into NPC [27] [28] [29]

APP and its cleavage products do not promote the proliferation and differentiation of post-mitotic neurons; rather the overexpression of either wild-type or mutant AβPP in post-mitotic neurons induces apoptotic death following their re-entry into the cell cycle (McPhie et al., 2003, J. Neurosci.). It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone, the adult equivalent of hCG, post-menopause and during andropause drives amyloid-β production (Bowen et al., 2004) and re-entry of post-mitotic neurons into the cell cycle.


Recently amyloid precursor protein (APP) origin was demonstrated with arthritogenic animals. The source noted is breakdown of immune complexes, where the amyloid aggregates are left degraded and binds together to form coil like structure that is not resorbed. Finally it induces secondary inflammation which may cause local damage.[30]


Amyloid precursor protein has been shown to interact with APBA3,[31][32] CLSTN1,[33][34] APPBP1,[35] Gelsolin,[36] BCAP31,[37] Caveolin 1,[38] FBLN1,[39] Collagen, type XXV, alpha 1,[40] APBB1,[41][42][43][44][45] APBA2,[31][34][46] APBA1,[31][41] APPBP2,[47] HSD17B10,[48] BLMH[49] and SHC1.[50]

One group of scientists reports that APP interacts with reelin, a protein implicated in a number of brain disorders, including Alzheimer's disease.[51]


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Further reading

  • 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 (1 Transduction): 91–102. doi:10.1111/j.1749-6632.1993.tb23035.x. PMID 8239320. 
  • 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. doi:10.1021/ar010031e. PMID 12069633. 
  • Annaert W, De Strooper B (2003). "A cell biological perspective on Alzheimer's disease.". Annu. Rev. Cell Dev. Biol. 18 (1): 25–51. doi:10.1146/annurev.cellbio.18.020402.142302. PMID 12142279. 
  • Koo EH (2003). "The beta-amyloid precursor protein (APP) and Alzheimer's disease: does the tail wag the dog?". Traffic 3 (11): 763–70. doi:10.1034/j.1600-0854.2002.31101.x. PMID 12383342. 
  • 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 (1): 258–65. doi:10.1111/j.1749-6632.2002.tb04824.x. PMID 12480759. 
  • 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. doi:10.1016/S1357-2725(03)00133-X. PMID 12824062. 
  • 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. doi:10.1002/jnr.20408. PMID 15672415. 
  • 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. doi:10.1111/j.0959-9673.2005.00434.x. PMID 15910549. 
  • Tickler AK, Wade JD, Separovic F (2005). "The role of Abeta peptides in Alzheimer's disease.". Protein Pept. Lett. 12 (6): 513–9. doi:10.2174/0929866054395905. PMID 16101387. 
  • Reinhard C, Hébert SS, De Strooper B (2006). "The amyloid-beta precursor protein: integrating structure with biological function.". EMBO J. 24 (23): 3996–4006. doi:10.1038/sj.emboj.7600860. PMC 1356301. PMID 16252002. 
  • 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. doi:10.1179/016164105X49436. PMID 16354549. 
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  • Vetrivel KS, Thinakaran G (2006). "Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments.". Neurology 66 (2 Suppl 1): S69–73. doi:10.1212/01.wnl.0000192107.17175.39. PMID 16432149. 
  • 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. PMID 16789686. 
  • Coulson EJ (2006). "Does the p75 neurotrophin receptor mediate Abeta-induced toxicity in Alzheimer's disease?". J. Neurochem. 98 (3): 654–60. doi:10.1111/j.1471-4159.2006.03905.x. PMID 16893414. 
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