View source for Amyloid precursor protein

{{Redirect|APPI|the former Professional Association of Independent Phonographic Producers|Union des Producteurs Phonographiques Français Indépendants}}
{{Infobox_gene}}

[[File:Relative transport of negatively charged, APP-C and glycine beads in the squid giant axon.jpg|thumb|(a) A low magnification image immediately after co-injection of red negatively charged and green glycine-conjugated beads showing the injection site, marked with an oil droplet, appearing as a round yellow sphere. Overlap of red and green fluorescence produces a yellow image. (b) At 50 min after injection, the red carboxylated beads have progressed in the anterograde direction (to the right) while the green glycine-conjugated beads have made no progress. (c)–(e) An axon co-injected with red APP-C beads and green glycine beads and imaged for 100 frames at 4 s intervals at 40× magnification. (c) Red channel (left) first frame; (center) 50 frames superimposed; (right) all 100 frames superimposed. Note the progression of individual beads towards the right, anterograde, side of the injection site heading towards the presynaptic terminal. (d) Two images of the green channel from the same video sequence; (left) first frame; (center) 100 frames superimposed. Note the lack of significant movement of the green glycine beads. (e) Both red and green channels from 100 frames superimposed of the same video as in (c) and (d). (f) Single bead trajectories at high magnification from a set of superimposed frames showing movements of beads.]]

'''Amyloid precursor protein''' ('''APP''') is an [[integral membrane protein]] expressed in many [[biological tissue|tissues]] and&nbsp;concentrated in the [[synapse]]s of [[neuron]]s. Its primary function is not known, though it has been implicated as a regulator of synapse formation,<ref name="Priller">{{cite journal | vauthors = Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J | title = Synapse formation and function is modulated by the amyloid precursor protein | journal = The Journal of Neuroscience | volume = 26 | issue = 27 | pages = 7212–21 | date = Jul 2006 | pmid = 16822978 | doi = 10.1523/JNEUROSCI.1450-06.2006 }}</ref> [[neural plasticity]]<ref name="Turner">{{cite journal | vauthors = Turner PR, O'Connor K, Tate WP, Abraham WC | title = Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory | journal = Progress in Neurobiology | volume = 70 | issue = 1 | pages = 1–32 | date = May 2003 | pmid = 12927332 | doi = 10.1016/S0301-0082(03)00089-3 }}</ref> and iron export.<ref name="Duce">{{cite journal | vauthors = Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI | title = Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease | journal = Cell | volume = 142 | issue = 6 | pages = 857–67 | date = Sep 2010 | pmid = 20817278 | pmc = 2943017 | doi = 10.1016/j.cell.2010.08.014 }}</ref> APP is best known as the precursor molecule whose [[proteolysis]] generates [[beta amyloid]] (Aβ), a polypeptide containing 37 to 49 [[amino acid]] residues, whose [[amyloid]] fibrillar form is the primary component of [[amyloid plaque]]s found in the brains of [[Alzheimer's disease]] patients.

== Genetics ==
APP is an ancient and highly [[Conserved sequence|conserved protein]].<ref name="Sarkar">{{cite journal | vauthors = Tharp WG, Sarkar IN | title = Origins of amyloid-β | journal = BMC Genomics | volume = 14 | issue = 1 | pages = 290 | date = April 2013 | pmid = 23627794 | doi = 10.1186/1471-2164-14-290 | pmc=3660159}}</ref>  In [[human]]s, the [[gene]] for APP is located on [[chromosome 21]] and contains 18 [[exon]]s spanning 290 [[kilobase]]s.<ref name="Yoshikai">{{cite journal | vauthors = Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y | title = Genomic organization of the human amyloid beta-protein precursor gene | journal = Gene | volume = 87 | issue = 2 | pages = 257–63 | date = Mar 1990 | pmid = 2110105 | doi = 10.1016/0378-1119(90)90310-N }}</ref><ref name="Lamb">{{cite journal | vauthors = Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, Pearson PL, Price DL, Gearhart JD | title = Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected] | journal = Nature Genetics | volume = 5 | issue = 1 | pages = 22–30 | date = Sep 1993 | pmid = 8220418 | doi = 10.1038/ng0993-22 }}</ref> Several [[alternative splicing]] isoforms of APP have been observed in humans, ranging in length from 639 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.<ref name="Matsui">{{cite journal | vauthors = Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, Frosch MP, Irizarry MC, Hyman BT | title = Expression of APP pathway mRNAs and proteins in Alzheimer's disease | journal = Brain Research | volume = 1161 | issue =  | pages = 116–23 | date = Aug 2007 | pmid = 17586478 | doi = 10.1016/j.brainres.2007.05.050 }}</ref> [[Homology (biology)|Homologous]] proteins have been identified in other organisms such as ''[[Drosophila]]'' (fruit flies), ''[[Caenorhabditis elegans|C. elegans]]'' (roundworms)<ref>{{Cite journal|last=Ewald|first=Collin Y.|last2=Li|first2=Chris|date=2012-04-01|title=Caenorhabditis elegans as a model organism to study APP function|journal=Experimental Brain Research|language=en|volume=217|issue=3–4|pages=397–411|doi=10.1007/s00221-011-2905-7|pmid=22038715|issn=0014-4819|pmc=3746071}}</ref>, and all [[mammal]]s.<ref name="Zheng">{{cite journal | vauthors = Zheng H, Koo EH | title = The amyloid precursor protein: beyond amyloid | journal = Molecular Neurodegeneration | volume = 1 | issue = 1 | pages = 5 | year = 2006 | pmid = 16930452 | pmc = 1538601 | doi = 10.1186/1750-1326-1-5 }}</ref> 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|native-state]] biological functions.<ref name="Zheng" />

Mutations in critical regions of amyloid precursor protein, including the region that generates amyloid beta (Aβ), cause familial susceptibility to Alzheimer's disease.<ref name="Goate">{{cite journal | vauthors = Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L | title = Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease | journal = Nature | volume = 349 | issue = 6311 | pages = 704–6 | date = Feb 1991 | pmid = 1671712 | doi = 10.1038/349704a0 }}</ref><ref name="Murrell">{{cite journal | vauthors = Murrell J, Farlow M, Ghetti B, Benson MD | title = A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease | journal = Science | volume = 254 | issue = 5028 | pages = 97–9 | date = Oct 1991 | pmid = 1925564 | doi = 10.1126/science.1925564 }}</ref><ref name="Chartier">{{cite journal | vauthors = Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J | title = Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene | journal = Nature | volume = 353 | issue = 6347 | pages = 844–6 | date = Oct 1991 | pmid = 1944558 | doi = 10.1038/353844a0 }}</ref> For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.<ref name="Citron">{{cite journal | vauthors = Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ | title = Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production | journal = Nature | volume = 360 | issue = 6405 | pages = 672–4 | date = Dec 1992 | pmid = 1465129 | doi = 10.1038/360672a0 }}</ref>

A mutation (A673T) in the APP gene protects against Alzheimer’s disease.  This substitution is adjacent to the beta secretase cleavage site and results in a 40% reduction in the formation of amyloid beta in vitro.<ref name=Jonsson_2012>{{cite journal | vauthors = Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K | title = A mutation in APP protects against Alzheimer's disease and age-related cognitive decline | journal = Nature | volume = 488 | issue = 7409 | pages = 96–9 | date = Aug 2012 | pmid = 22801501 | doi = 10.1038/nature11283 | laysummary = https://www.nytimes.com/2012/07/12/health/research/rare-gene-mutation-is-found-to-stave-off-alzheimers.html | laysource = The New York Times }}</ref>

== Structure ==
[[File:2fjz app.png|left|thumb|250px|upright=1.2|The metal-binding domain of APP with a bound [[copper]] ion. The [[side chain]]s 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.]]
[[Image:1rw6 e2 app.png|left|thumb|upright=1.2|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]] [[proteoglycan]]s.<ref name="WangHa">{{PDB|1RW6}}; {{cite journal | vauthors = Wang Y, Ha Y | title = The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain | journal = Molecular Cell | volume = 15 | issue = 3 | pages = 343–53 | date = Aug 2004 | pmid = 15304215 | doi = 10.1016/j.molcel.2004.06.037 }}</ref> ]]
A number of distinct, largely independently-[[protein folding|folding]] structural [[protein domain|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.<ref name="Dahms">{{cite journal | vauthors = Dahms SO, Hoefgen S, Roeser D, Schlott B, Gührs KH, Than ME | title = Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 12 | pages = 5381–6 | date = Mar 2010 | pmid = 20212142 | pmc = 2851805 | doi = 10.1073/pnas.0911326107 }}; see also PDB ID {{PDB2|3KTM}}</ref> A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain.<ref name="Sisodia">{{cite journal | vauthors = Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL | title = Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system | journal = The Journal of Neuroscience | volume = 13 | issue = 7 | pages = 3136–42 | date = Jul 1993 | pmid = 8331390 | doi =  }}</ref> The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the [[growth factor-like domain]],<ref name="Rossjohn">{{cite journal | vauthors = Rossjohn J, Cappai R, Feil SC, Henry A, McKinstry WJ, Galatis D, Hesse L, Multhaup G, Beyreuther K, Masters CL, Parker MW | title = Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein | journal = Nature Structural Biology | volume = 6 | issue = 4 | pages = 327–31 | date = Apr 1999 | pmid = 10201399 | doi = 10.1038/7562 }}; see also PDB ID {{PDB2|1MWP}}</ref> the [[copper]]-binding domain,<ref name="Kong">{{cite journal | vauthors = Kong GK, Adams JJ, Harris HH, Boas JF, Curtain CC, Galatis D, Masters CL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW | title = Structural studies of the Alzheimer's amyloid precursor protein copper-binding domain reveal how it binds copper ions | journal = Journal of Molecular Biology | volume = 367 | issue = 1 | pages = 148–61 | date = Mar 2007 | pmid = 17239395 | doi = 10.1016/j.jmb.2006.12.041 }}; See also 2007 PDB IDs {{PDB2|2FJZ}}, {{PDB2|2FK2}}, {{PDB2|2FKL}}.</ref> the complete E1 domain<ref name="Dahms"/> and the E2 domain.<ref name="WangHa"/>

== Post-translational processing ==
APP undergoes extensive [[post-translational modification]] including [[glycosylation]], [[phosphorylation]], [[sialylation]], and [[tyrosine sulfation]], as well as many types of [[proteolysis|proteolytic]] processing to generate peptide fragments.<ref name="De Strooper">{{cite journal | vauthors = De Strooper B, Annaert W | title = Proteolytic processing and cell biological functions of the amyloid precursor protein | journal = Journal of Cell Science | volume = 113 | issue =  11| pages = 1857–70 | date = Jun 2000 | pmid = 10806097 | doi =  }}</ref> It is commonly cleaved by [[protease]]s in the [[secretase]] family; [[alpha secretase]] and [[beta secretase]] both remove nearly the entire extracellular domain to release membrane-anchored [[C-terminus|carboxy-terminal]] fragments that may be associated with [[apoptosis]].<ref name="Zheng" /> Cleavage by [[gamma secretase]] within the membrane-spanning domain after beta-secretase cleavage 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.<ref name="Chen">{{cite journal | vauthors = 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 | title = TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity | journal = Nature | volume = 440 | issue = 7088 | pages = 1208–12 | date = Apr 2006 | pmid = 16641999 | doi = 10.1038/nature04667 }}</ref>

The amyloidogenic processing of APP has been linked to its presence in [[lipid raft]]s. 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.<ref name="Ehehalt">{{cite journal | vauthors = Ehehalt R, Keller P, Haass C, Thiele C, Simons K | title = Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts | journal = The Journal of Cell Biology | volume = 160 | issue = 1 | pages = 113–23 | date = Jan 2003 | pmid = 12515826 | pmc = 2172747 | doi = 10.1083/jcb.200207113 }}</ref> Gamma secretase activity has also been associated with lipid rafts.<ref name="Vetrivel">{{cite journal | vauthors = Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G | title = Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes | journal = The Journal of Biological Chemistry | volume = 279 | issue = 43 | pages = 44945–54 | date = Oct 2004 | pmid = 15322084 | pmc = 1201506 | doi = 10.1074/jbc.M407986200 }}</ref> 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.<ref name="Riddell">{{cite journal | vauthors = Riddell DR, Christie G, Hussain I, Dingwall C | title = Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts | journal = Current Biology | volume = 11 | issue = 16 | pages = 1288–93 | date = Aug 2001 | pmid = 11525745 | doi = 10.1016/S0960-9822(01)00394-3 }}</ref>

== 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;<ref name="Priller" /> its [[gene expression|expression]] is [[gene regulation|upregulated]] during neuronal [[cell differentiation|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.<ref name="Zheng" /> In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface [[transmembrane receptor|receptor]] protein [[Notch signaling|Notch]].<ref name="Selkoe">{{cite journal | vauthors = Selkoe D, Kopan R | title = Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration | journal = Annual Review of Neuroscience | volume = 26 | issue = 1 | pages = 565–97 | year = 2003 | pmid = 12730322 | doi = 10.1146/annurev.neuro.26.041002.131334 }}</ref>

APP [[knockout mice]] are viable and have relatively minor [[phenotype|phenotypic]] effects including impaired long-term potentiation and memory loss without general neuron loss.<ref name="Phinney">{{cite journal | vauthors = Phinney AL, Calhoun ME, Wolfer DP, Lipp HP, Zheng H, Jucker M | title = No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice | journal = Neuroscience | volume = 90 | issue = 4 | pages = 1207–16 | year = 1999 | pmid = 10338291 | doi = 10.1016/S0306-4522(98)00645-9 }}</ref> On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.<ref name="Matsuyama">{{cite journal | vauthors = Matsuyama S, Teraoka R, Mori H, Tomiyama T | year = 2007 | title = Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice | url = | journal = NeuroReport | volume = 18 | issue = 10| pages = 1083–7 | pmid = 17558301 | doi=10.1097/WNR.0b013e3281e72b18}}</ref>

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.<ref name="pmid18648325">{{cite journal | vauthors = 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 = Journal of Neuropathology and Experimental Neurology | volume = 67 | issue = 8 | pages = 773–83 | date = Aug 2008 | pmid = 18648325 | pmc = 3334532 | doi = 10.1097/NEN.0b013e318180ec47 }}</ref> 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.

=== Anterograde neuronal transport ===
Molecules synthesized in the cell bodies of neurons must be conveyed outward to the distal synapses. This is accomplished via [[Axoplasmic transport#Fast and slow transport|fast anterograde transport]]. It has been found that APP can mediate interaction between cargo and [[kinesin]] and thus facilitate this transport. Specifically, a short peptide 15-amino-acid sequence from the cytoplasmic carboxy-terminus is necessary for interaction with the motor protein.<ref>{{cite journal | vauthors = Satpute-Krishnan P, DeGiorgis JA, Conley MP, Jang M, Bearer EL | title = A peptide zipcode sufficient for anterograde transport within amyloid precursor protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 44 | pages = 16532–7 | date = Oct 2006 | pmid = 17062754 | doi = 10.1073/pnas.0607527103 | pmc=1621108}}</ref>

Additionally, it has been shown that the interaction between APP and kinesin is specific to the peptide sequence of APP.<ref>{{cite journal | vauthors = Seamster PE, Loewenberg M, Pascal J, Chauviere A, Gonzales A, Cristini V, Bearer EL | title = Quantitative measurements and modeling of cargo-motor interactions during fast transport in the living axon | journal = Physical Biology | volume = 9 | issue = 5 | pages = 055005 | date = Oct 2012 | pmid = 23011729 | pmc = 3625656 | doi = 10.1088/1478-3975/9/5/055005 }}</ref> In a recent experiment involving transport of peptide-conjugated colored [[Microsphere|beads]], controls were conjugated to a single amino acid, [[glycine]], such that they display the same terminal carboxylic acid group as APP without the intervening 15-amino-acid sequence mentioned above. The control beads were not motile, which demonstrated that the terminal [[Carboxylic acid|COOH]] moiety of peptides is not sufficient to mediate transport.

=== 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.<ref name="Duce"/>  It has been shown that a [[single nucleotide polymorphism]] in the [[5'UTR]] of APP [[mRNA]] can disrupt its translation.<ref name="pmid19021541">{{cite journal | vauthors = Rogers JT, Bush AI, Cho HH, Smith DH, Thomson AM, Friedlich AL, Lahiri DK, Leedman PJ, Huang X, Cahill CM | title = Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease | journal = Biochemical Society Transactions | volume = 36 | issue = Pt 6 | pages = 1282–7 | date = Dec 2008 | pmid = 19021541 | pmc = 2746665 | doi = 10.1042/BST0361282 }}</ref>

The hypothesis that APP has ferroxidase activity in its E2 domain and facilitates export of Fe(II) is possibly incorrect since the proposed ferroxidase site of APP located in the E2 domain does not have ferroxidase activity.<ref name="pmid22916096">{{cite journal | vauthors = Ebrahimi KH, Hagedoorn PL, Hagen WR | title = A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP) does not catalytically oxidize iron | journal = PLOS ONE | volume = 7 | issue = 8 | pages = e40287 | year = 2012 | pmid = 22916096 | pmc = 3419245 | doi = 10.1371/journal.pone.0040287 }}</ref><ref name="pmid23977245">{{cite journal | vauthors = Honarmand Ebrahimi K, Dienemann C, Hoefgen S, Than ME, Hagedoorn PL, Hagen WR | title = The amyloid precursor protein (APP) does not have a ferroxidase site in its E2 domain | journal = PLOS ONE | volume = 8 | issue = 8 | pages = e72177 | year = 2013 | pmid = 23977245 | doi = 10.1371/journal.pone.0072177 | pmc=3747053}}</ref>

As APP does not possess ferroxidase activity within its E2 domain, the mechanism of APP-modulated iron efflux from ferroportin has come under scrutiny. One model suggests that APP acts to stabilize the iron efflux protein ferroportin in the plasma membrane of cells thereby increasing the total number of ferroportin molecules at the membrane. These iron-transporters can then be activated by known mammalian ferroxidases (i.e. ceruloplasmin or hephaestin).<ref>{{cite journal | vauthors = McCarthy RC, Park YH, Kosman DJ | title = sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin | journal = EMBO Reports | volume = 15 | issue = 7 | pages = 809–15 | date = Jul 2014 | pmid = 24867889 | doi = 10.15252/embr.201338064 | pmc=4196985}}</ref>

=== Hormonal regulation ===
The amyloid-β precursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role in the [[endocrinology of reproduction]] – with the differential processing of AβPP by secretases regulating [[human embryonic stem cell]] (hESC) [[Cell proliferation|proliferation]] as well as their [[Cellular differentiation|differentiation]] into neural precursor cells (NPC). The pregnancy hormone [[human chorionic gonadotropin]] (hCG) increases AβPP expression<ref name="pmid17959150">{{cite journal | vauthors = Porayette P, Gallego MJ, Kaltcheva MM, Meethal SV, Atwood CS | title = Amyloid-beta precursor protein expression and modulation in human embryonic stem cells: a novel role for human chorionic gonadotropin | journal = Biochemical and Biophysical Research Communications | volume = 364 | issue = 3 | pages = 522–7 | date = Dec 2007 | pmid = 17959150 | doi = 10.1016/j.bbrc.2007.10.021 }}</ref> and hESC proliferation while [[progesterone]] directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC.<ref name="pmid19542221">{{cite journal | vauthors = Porayette P, Gallego MJ, Kaltcheva MM, Bowen RL, Vadakkadath Meethal S, Atwood CS | title = Differential processing of amyloid-beta precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells | journal = The Journal of Biological Chemistry | volume = 284 | issue = 35 | pages = 23806–17 | date = Aug 2009 | pmid = 19542221 | pmc = 2749153 | doi = 10.1074/jbc.M109.026328 }}</ref><ref name="pmid18803462">{{cite journal | vauthors = Gallego MJ, Porayette P, Kaltcheva MM, Meethal SV, Atwood CS | title = Opioid and progesterone signaling is obligatory for early human embryogenesis | journal = Stem Cells and Development | volume = 18 | issue = 5 | pages = 737–40 | date = Jun 2009 | pmid = 18803462 | pmc = 2891507 | doi = 10.1089/scd.2008.0190 }}</ref><ref name="pmid20836886">{{cite journal | vauthors = Gallego MJ, Porayette P, Kaltcheva MM, Bowen RL, Vadakkadath Meethal S, Atwood CS | title = The pregnancy hormones human chorionic gonadotropin and progesterone induce human embryonic stem cell proliferation and differentiation into neuroectodermal rosettes | journal = Stem Cell Research & Therapy | volume = 1 | issue = 4 | pages = 28 | year = 2010 | pmid = 20836886 | pmc = 2983441 | doi = 10.1186/scrt28 }}</ref>

AβPP and its [[Bond cleavage|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]].<ref name="pmid12890786">{{cite journal | vauthors = McPhie DL, Coopersmith R, Hines-Peralta A, Chen Y, Ivins KJ, Manly SP, Kozlowski MR, Neve KA, Neve RL | title = DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3 | journal = The Journal of Neuroscience | volume = 23 | issue = 17 | pages = 6914–27 | date = Jul 2003 | pmid = 12890786 | doi =  }}</ref>  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<ref name="pmid14871891">{{cite journal | vauthors = Bowen RL, Verdile G, Liu T, Parlow AF, Perry G, Smith MA, Martins RN, Atwood CS | title = Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition | journal = The Journal of Biological Chemistry | volume = 279 | issue = 19 | pages = 20539–45 | date = May 2004 | pmid = 14871891 | doi = 10.1074/jbc.M311993200 }}</ref> and re-entry of post-mitotic neurons into the cell cycle.

== Interactions ==
Amyloid precursor protein has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[APBA1]],<ref name=pmid12196555/><ref name=pmid8887653/>
* [[APBA2]],<ref name=pmid12196555/><ref name=pmid12972431/><ref name=pmid9890987>{{cite journal | vauthors = Tomita S, Ozaki T, Taru H, Oguchi S, Takeda S, Yagi Y, Sakiyama S, Kirino Y, Suzuki T | title = Interaction of a neuron-specific protein containing PDZ domains with Alzheimer's amyloid precursor protein | journal = The Journal of Biological Chemistry | volume = 274 | issue = 4 | pages = 2243–54 | date = Jan 1999 | pmid = 9890987 | doi = 10.1074/jbc.274.4.2243 }}</ref>
* [[APBA3]],<ref name=pmid12196555>{{cite journal | vauthors = Biederer T, Cao X, Südhof TC, Liu X | title = Regulation of APP-dependent transcription complexes by Mint/X11s: differential functions of Mint isoforms | journal = The Journal of Neuroscience | volume = 22 | issue = 17 | pages = 7340–51 | date = Sep 2002 | pmid = 12196555 | doi =  }}</ref><ref name=pmid10049767>{{cite journal | vauthors = Tanahashi H, Tabira T | title = X11L2, a new member of the X11 protein family, interacts with Alzheimer's beta-amyloid precursor protein | journal = Biochemical and Biophysical Research Communications | volume = 255 | issue = 3 | pages = 663–7 | date = Feb 1999 | pmid = 10049767 | doi = 10.1006/bbrc.1999.0265 }}</ref>
* [[APBB1]],<ref name=pmid8887653>{{cite journal | vauthors = Borg JP, Ooi J, Levy E, Margolis B | title = The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein | journal = Molecular and Cellular Biology | volume = 16 | issue = 11 | pages = 6229–41 | date = Nov 1996 | pmid = 8887653 | pmc = 231626 | doi =  10.1128/mcb.16.11.6229}}</ref><ref name=pmid9045663>{{cite journal | vauthors = Zambrano N, Buxbaum JD, Minopoli G, Fiore F, De Candia P, De Renzis S, Faraonio R, Sabo S, Cheetham J, Sudol M, Russo T | title = Interaction of the phosphotyrosine interaction/phosphotyrosine binding-related domains of Fe65 with wild-type and mutant Alzheimer's beta-amyloid precursor proteins | journal = The Journal of Biological Chemistry | volume = 272 | issue = 10 | pages = 6399–405 | date = Mar 1997 | pmid = 9045663 | doi = 10.1074/jbc.272.10.6399 }}</ref><ref name=pmid8855266>{{cite journal | vauthors = Guénette SY, Chen J, Jondro PD, Tanzi RE | title = Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 20 | pages = 10832–7 | date = Oct 1996 | pmid = 8855266 | pmc = 38241 | doi = 10.1073/pnas.93.20.10832 }}</ref><ref name=pmid10081969>{{cite journal | vauthors = Tanahashi H, Tabira T | title = Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein | journal = Neuroscience Letters | volume = 261 | issue = 3 | pages = 143–6 | date = Feb 1999 | pmid = 10081969 | doi = 10.1016/S0304-3940(98)00995-1 }}</ref><ref name=pmid9837937>{{cite journal | vauthors = Trommsdorff M, Borg JP, Margolis B, Herz J | title = Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein | journal = The Journal of Biological Chemistry | volume = 273 | issue = 50 | pages = 33556–60 | date = Dec 1998 | pmid = 9837937 | doi = 10.1074/jbc.273.50.33556 }}</ref>
* [[APPBP1]],<ref name=pmid8626687>{{cite journal | vauthors = Chow N, Korenberg JR, Chen XN, Neve RL | title = APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein | journal = The Journal of Biological Chemistry | volume = 271 | issue = 19 | pages = 11339–46 | date = May 1996 | pmid = 8626687 | doi = 10.1074/jbc.271.19.11339 }}</ref>
* [[APPBP2]],<ref name=pmid9843960>{{cite journal | vauthors = Zheng P, Eastman J, Vande Pol S, Pimplikar SW | title = PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 25 | pages = 14745–50 | date = Dec 1998 | pmid = 9843960 | pmc = 24520 | doi = 10.1073/pnas.95.25.14745 }}</ref>
* [[BCAP31]],<ref name=pmid12529377>{{cite journal | vauthors = Wang B, Nguyen M, Breckenridge DG, Stojanovic M, Clemons PA, Kuppig S, Shore GC | title = Uncleaved BAP31 in association with A4 protein at the endoplasmic reticulum is an inhibitor of Fas-initiated release of cytochrome c from mitochondria | journal = The Journal of Biological Chemistry | volume = 278 | issue = 16 | pages = 14461–8 | date = Apr 2003 | pmid = 12529377 | doi = 10.1074/jbc.M209684200 }}</ref>
* [[BLMH]]<ref name=pmid10973933>{{cite journal | vauthors = Lefterov IM, Koldamova RP, Lazo JS | title = Human bleomycin hydrolase regulates the secretion of amyloid precursor protein | journal = FASEB Journal | volume = 14 | issue = 12 | pages = 1837–47 | date = Sep 2000 | pmid = 10973933 | doi = 10.1096/fj.99-0938com }}</ref>
* [[CLSTN1]],<ref name=pmid12972431>{{cite journal | vauthors = Araki Y, Tomita S, Yamaguchi H, Miyagi N, Sumioka A, Kirino Y, Suzuki T | title = Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism | journal = The Journal of Biological Chemistry | volume = 278 | issue = 49 | pages = 49448–58 | date = Dec 2003 | pmid = 12972431 | doi = 10.1074/jbc.M306024200 }}</ref><ref name=pmid15037614>{{cite journal | vauthors = Araki Y, Miyagi N, Kato N, Yoshida T, Wada S, Nishimura M, Komano H, Yamamoto T, De Strooper B, Yamamoto K, Suzuki T | title = Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 23 | pages = 24343–54 | date = Jun 2004 | pmid = 15037614 | doi = 10.1074/jbc.M401925200 }}</ref>
* [[Caveolin 1|CAV1]],<ref name=pmid9553108>{{cite journal | vauthors = Ikezu T, Trapp BD, Song KS, Schlegel A, Lisanti MP, Okamoto T | title = Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein | journal = The Journal of Biological Chemistry | volume = 273 | issue = 17 | pages = 10485–95 | date = Apr 1998 | pmid = 9553108 | doi = 10.1074/jbc.273.17.10485 }}</ref>
* [[Collagen, type XXV, alpha 1|COL25A1]],<ref name=pmid11927537>{{cite journal | vauthors = Hashimoto T, Wakabayashi T, Watanabe A, Kowa H, Hosoda R, Nakamura A, Kanazawa I, Arai T, Takio K, Mann DM, Iwatsubo T | title = CLAC: a novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC-P/collagen type XXV | journal = The EMBO Journal | volume = 21 | issue = 7 | pages = 1524–34 | date = Apr 2002 | pmid = 11927537 | pmc = 125364 | doi = 10.1093/emboj/21.7.1524 }}</ref>
* [[FBLN1]],<ref name=pmid11238726>{{cite journal | vauthors = Ohsawa I, Takamura C, Kohsaka S | title = Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and modulates its physiological function | journal = Journal of Neurochemistry | volume = 76 | issue = 5 | pages = 1411–20 | date = Mar 2001 | pmid = 11238726 | doi = 10.1046/j.1471-4159.2001.00144.x }}</ref>
* [[Gelsolin|GSN]],<ref name=pmid10329371>{{cite journal | vauthors = Chauhan VP, Ray I, Chauhan A, Wisniewski HM | title = Binding of gelsolin, a secretory protein, to amyloid beta-protein | journal = Biochemical and Biophysical Research Communications | volume = 258 | issue = 2 | pages = 241–6 | date = May 1999 | pmid = 10329371 | doi = 10.1006/bbrc.1999.0623 }}</ref>
* [[HSD17B10]],<ref name=pmid9338779>{{cite journal | vauthors = Yan SD, Fu J, Soto C, Chen X, Zhu H, Al-Mohanna F, Collison K, Zhu A, Stern E, Saido T, Tohyama M, Ogawa S, Roher A, Stern D | title = An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease | journal = Nature | volume = 389 | issue = 6652 | pages = 689–95 | date = Oct 1997 | pmid = 9338779 | doi = 10.1038/39522 }}</ref> and
* [[SHC1]].<ref name=pmid11877420>{{cite journal | vauthors = Tarr PE, Roncarati R, Pelicci G, Pelicci PG, D'Adamio L | title = Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc | journal = The Journal of Biological Chemistry | volume = 277 | issue = 19 | pages = 16798–804 | date = May 2002 | pmid = 11877420 | doi = 10.1074/jbc.M110286200 }}</ref>
{{Div col end}}

APP interacts with [[reelin]], a protein implicated in a number of brain disorders, including Alzheimer's disease.<ref name="pmid19515914">{{cite journal | vauthors = Hoe HS, Lee KJ, Carney RS, Lee J, Markova A, Lee JY, Howell BW, Hyman BT, Pak DT, Bu G, Rebeck GW | title = Interaction of reelin with amyloid precursor protein promotes neurite outgrowth | journal = The Journal of Neuroscience | volume = 29 | issue = 23 | pages = 7459–73 | date = Jun 2009 | pmid = 19515914 | pmc = 2759694 | doi = 10.1523/JNEUROSCI.4872-08.2009 | laysummary = http://www.alzforum.org/new/detail.asp?id=2170 | laysource = Alzheimer Research Forum }}</ref>
{{Clear}}

== References ==
{{Reflist|33em}}

== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Beyreuther K, Pollwein P, Multhaup G, Mönning U, König G, Dyrks T, Schubert W, Masters CL | title = Regulation and expression of the Alzheimer's beta/A4 amyloid protein precursor in health, disease, and Down's syndrome | journal = Annals of the New York Academy of Sciences | volume = 695 | issue = 1 Transduction | pages = 91–102 | date = Sep 1993 | pmid = 8239320 | doi = 10.1111/j.1749-6632.1993.tb23035.x }}
* {{cite journal | vauthors = Straub JE, Guevara J, Huo S, Lee JP | title = Long time dynamic simulations: exploring the folding pathways of an Alzheimer's amyloid Abeta-peptide | journal = Accounts of Chemical Research | volume = 35 | issue = 6 | pages = 473–81 | date = Jun 2002 | pmid = 12069633 | doi = 10.1021/ar010031e }}
* {{cite journal | vauthors = Annaert W, De Strooper B | title = A cell biological perspective on Alzheimer's disease | journal = Annual Review of Cell and Developmental Biology | volume = 18 | issue = 1 | pages = 25–51 | year = 2003 | pmid = 12142279 | doi = 10.1146/annurev.cellbio.18.020402.142302 }}
* {{cite journal | vauthors = Koo EH | title = The beta-amyloid precursor protein (APP) and Alzheimer's disease: does the tail wag the dog? | journal = Traffic | volume = 3 | issue = 11 | pages = 763–70 | date = Nov 2002 | pmid = 12383342 | doi = 10.1034/j.1600-0854.2002.31101.x }}
* {{cite journal | vauthors = Van Nostrand WE, Melchor JP, Romanov G, Zeigler K, Davis J | title = Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor | journal = Annals of the New York Academy of Sciences | volume = 977 | issue = 1 | pages = 258–65 | date = Nov 2002 | pmid = 12480759 | doi = 10.1111/j.1749-6632.2002.tb04824.x }}
* {{cite journal | vauthors = Ling Y, Morgan K, Kalsheker N | title = Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease | journal = The International Journal of Biochemistry & Cell Biology | volume = 35 | issue = 11 | pages = 1505–35 | date = Nov 2003 | pmid = 12824062 | doi = 10.1016/S1357-2725(03)00133-X }}
* {{cite journal | vauthors = Kerr ML, Small DH | title = Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development | journal = Journal of Neuroscience Research | volume = 80 | issue = 2 | pages = 151–9 | date = Apr 2005 | pmid = 15672415 | doi = 10.1002/jnr.20408 }}
* {{cite journal | vauthors = Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX | title = Metals and amyloid-beta in Alzheimer's disease | journal = International Journal of Experimental Pathology | volume = 86 | issue = 3 | pages = 147–59 | date = Jun 2005 | pmid = 15910549 | pmc = 2517409 | doi = 10.1111/j.0959-9673.2005.00434.x }}
* {{cite journal | vauthors = Tickler AK, Wade JD, Separovic F | title = The role of Abeta peptides in Alzheimer's disease | journal = Protein and Peptide Letters | volume = 12 | issue = 6 | pages = 513–9 | date = Aug 2005 | pmid = 16101387 | doi = 10.2174/0929866054395905 }}
* {{cite journal | vauthors = Reinhard C, Hébert SS, De Strooper B | title = The amyloid-beta precursor protein: integrating structure with biological function | journal = The EMBO Journal | volume = 24 | issue = 23 | pages = 3996–4006 | date = Dec 2005 | pmid = 16252002 | pmc = 1356301 | doi = 10.1038/sj.emboj.7600860 }}
* {{cite journal | vauthors = Watson D, Castaño E, Kokjohn TA, Kuo YM, Lyubchenko Y, Pinsky D, Connolly ES, Esh C, Luehrs DC, Stine WB, Rowse LM, Emmerling MR, Roher AE | title = Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease | journal = Neurological Research | volume = 27 | issue = 8 | pages = 869–81 | date = Dec 2005 | pmid = 16354549 | doi = 10.1179/016164105X49436 }}
* {{cite journal | vauthors = Calinisan V, Gravem D, Chen RP, Brittin S, Mohandas N, Lecomte MC, Gascard P | title = New insights into potential functions for the protein 4.1 superfamily of proteins in kidney epithelium | journal = Frontiers in Bioscience | volume = 11 | issue = 1 | pages = 1646–66 | year = 2006 | pmid = 16368544 | doi = 10.2741/1911 | url = https://digital.library.unt.edu/ark:/67531/metadc892527/ }}
* {{cite journal | vauthors = Vetrivel KS, Thinakaran G | title = Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments | journal = Neurology | volume = 66 | issue = 2 Suppl 1 | pages = S69–73 | date = Jan 2006 | pmid = 16432149 | doi = 10.1212/01.wnl.0000192107.17175.39 }}
* {{cite journal | vauthors = Gallo C, Orlassino R, Vineis C | title = [Recurrent intraparenchimal haemorrhages in a patient with cerebral amyloidotic angiopathy: description of one autopsy case] | journal = Pathologica | volume = 98 | issue = 1 | pages = 44–7 | date = Feb 2006 | pmid = 16789686 | doi =  }}
* {{cite journal | vauthors = Coulson EJ | title = Does the p75 neurotrophin receptor mediate Abeta-induced toxicity in Alzheimer's disease? | journal = Journal of Neurochemistry | volume = 98 | issue = 3 | pages = 654–60 | date = Aug 2006 | pmid = 16893414 | doi = 10.1111/j.1471-4159.2006.03905.x }}
* {{cite journal | vauthors = Menéndez-González M, Pérez-Pinera P, Martínez-Rivera M, Calatayud MT, Blázquez Menes B | title = APP processing and the APP-KPI domain involvement in the amyloid cascade | journal = Neuro-Degenerative Diseases | volume = 2 | issue = 6 | pages = 277–83 | year = 2006 | pmid = 16909010 | doi = 10.1159/000092315 }}
* {{cite journal | vauthors = Neve RL, McPhie DL | title = Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis | journal = Biochimica et Biophysica Acta | volume = 1772 | issue = 4 | pages = 430–7 | date = Apr 2007 | pmid = 17113271 | pmc = 1862818 | doi = 10.1016/j.bbadis.2006.10.008 }}
* {{cite journal | vauthors = Chen X, Stern D, Yan SD | title = Mitochondrial dysfunction and Alzheimer's disease | journal = Current Alzheimer Research | volume = 3 | issue = 5 | pages = 515–20 | date = Dec 2006 | pmid = 17168650 | doi = 10.2174/156720506779025215 }}
* {{cite journal | vauthors = Caltagarone J, Jing Z, Bowser R | title = Focal adhesions regulate Abeta signaling and cell death in Alzheimer's disease | journal = Biochimica et Biophysica Acta | volume = 1772 | issue = 4 | pages = 438–45 | date = Apr 2007 | pmid = 17215111 | pmc = 1876750 | doi = 10.1016/j.bbadis.2006.11.007 }}
* {{cite journal | vauthors = Wolfe MS | title = When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease | journal = EMBO Reports | volume = 8 | issue = 2 | pages = 136–40 | date = Feb 2007 | pmid = 17268504 | pmc = 1796780 | doi = 10.1038/sj.embor.7400896 }}
{{Refend}}

== External links ==
{{Commons category|Alzheimer's amyloid B-protein precursor, APPI|APP}}
* [https://www.ncbi.nlm.nih.gov/books/NBK1236/  GeneReviews/NCBI/NIH/UW entry on Early-Onset Familial Alzheimer Disease]
* {{MeshName|Amyloid+Protein+Precursor}}
* [https://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)]
* {{UCSC gene info|APP}}

{{PDB Gallery|geneid=351}}
{{Amyloidosis}}

[[Category:Alzheimer's disease]]
[[Category:Single-pass transmembrane proteins]]
[[Category:Neurochemistry]]
[[Category:Amyloidosis]]
[[Category:Precursor proteins]]