View source for Beta-secretase 1

{{Infobox_gene}}

'''Beta-secretase 1''' ('''BACE1'''), also known as '''beta-site amyloid precursor protein cleaving enzyme 1''', '''beta-site APP cleaving enzyme 1''', '''membrane-associated aspartic protease 2''', '''memapsin-2''', '''aspartyl protease 2''', and '''ASP2''', is an [[enzyme]] that in humans is encoded by the ''BACE1'' [[gene]].<ref name="pmid10531052">{{cite journal | vauthors = Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M | title = Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE | journal = Science | volume = 286 | issue = 5440 | pages = 735–41 | date = Oct 1999 | pmid = 10531052 | doi = 10.1126/science.286.5440.735 }}</ref>

BACE1 is an aspartic-acid [[protease]] important in the formation of [[myelin sheath]]s in peripheral nerve cells.<ref name="pmid16990514">{{cite journal | vauthors = Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C | title = Control of peripheral nerve myelination by the beta-secretase BACE1 | journal = Science | volume = 314 | issue = 5799 | pages = 664–6 | date = Oct 2006 | pmid = 16990514 | doi = 10.1126/science.1132341 | laysource = The Scientist | layurl = http://www.the-scientist.com/news/display/24841/ | bibcode = 2006Sci...314..664W }}</ref> The [[transmembrane protein]] contains two active site [[aspartate]] residues in its [[extracellular]] [[protein domain]] and may function as a [[protein dimer|dimer]].

== Role in Alzheimer's disease ==
[[Image:APP processing.png|thumb|294px|left|Processing of the amyloid precursor protein]]

Generation of the 40 or 42 [[amino acid]]-long [[amyloid beta|amyloid-β]] [[peptides]] that aggregate in the [[brain]] of Alzheimer's patients requires two sequential cleavages of the [[amyloid precursor protein]] (APP). Extracellular cleavage of APP by BACE1 creates a soluble extracellular fragment and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by [[gamma-secretase|γ-secretase]] releases the intracellular domain of APP and produces amyloid-β.  Since [[gamma-secretase]] cleaves APP closer to the [[cell membrane]] than BACE1 does, it removes a fragment of the amyloid-β peptide. Initial cleavage of APP by α-secretase rather than BACE1 prevents eventual generation of amyloid-β.

Unlike APP and the [[presenilin]] proteins important in γ-secretase, no known [[mutations]] in the [[gene]] encoding BACE1 cause early-onset, [[familial Alzheimer's disease]], which is a rare form of the disorder.  However, levels of this enzyme have been shown to be elevated in the far more common late-onset sporadic Alzheimer's. The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown.  [[BACE2]] is a close [[homology (biology)|homolog]] of BACE1 with no reported APP cleavage ''in vivo''.

However a single residue mutation in APP reduces the ability of BACE1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimers and other cognitive declines.<ref name=APP2012>{{cite news |url=http://pennstatehershey.adam.com/content.aspx?productId=16&gid=54569 |title=Alzheimer's-fighting gene may inspire treatments |date=July 2012 }}</ref><ref name=Jonsson2012>{{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 | url = http://www.nature.com/nature/journal/vaop/ncurrent/full/nature11283.html | bibcode = 2012Natur.488...96J }}</ref>

== BACE inhibitors ==

Drugs to block this enzyme (BACE inhibitors) in theory would prevent the buildup of beta-amyloid and (per the [[Amyloid hypothesis]]) may help slow or stop Alzheimers disease.

===For Alzheimers disease===
Several companies are in the early stages of development and testing of this potential class of treatment.<ref name="pmid16644763">{{cite journal | vauthors = Walker LC, Rosen RF | title = Alzheimer therapeutics-what after the cholinesterase inhibitors? | journal = Age and Ageing | volume = 35 | issue = 4 | pages = 332–5 | date = Jul 2006 | pmid = 16644763 | doi = 10.1093/ageing/afl009 }}</ref><ref name="pmid17685503">{{cite journal | vauthors = Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL, Reynolds CH, Tounge BA, Luo C, Scott MK, Huang Y, Braeken M, Pieters SM, Berthelot DJ, Masure S, Bruinzeel WD, Jordan AD, Parker MH, Boyd RE, Qu J, Alexander RS, Brenneman DE, Reitz AB | title = 2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 18 | pages = 4261–4 | date = Sep 2007 | pmid = 17685503 | doi = 10.1021/jm0705408 }}</ref> In March 2008 phase I results were reported for CoMentis Inc's candidate CTS-21166.<ref>{{cite news |url=http://www.alzforum.org/new/detail.asp?id=1790 |title=CoMentis BACE Inhibitor Debuts |date=April 2008 }}</ref>

In April 2012 [[Merck & Co.]], Inc reported phase I results for its candidate [[verubecestat]] (MK-8931).<ref>{{cite news |url=http://www.merck.com/newsroom/news-release-archive/research-and-development/2012_0427.html |title=Merck Presents Results of a Phase I Clinical Trial Evaluating Investigational BACE inhibitor MK-8931 at American Academy of Neurology |date=April 2012 |deadurl=yes |archiveurl=https://web.archive.org/web/20120728084446/http://www.merck.com/newsroom/news-release-archive/research-and-development/2012_0427.html |archivedate=2012-07-28 |df= }}</ref> Merck began a Phase II/III trial of MK-8931 in December, 2012 estimated to be completed in July 2019.<ref>{{cite news |url=http://www.mercknewsroom.com/press-release/research-and-development-news/merck-initiates-phase-iiiii-study-investigational-bace-i |title=Merck Initiates Phase II/III Study of Investigational BACE Inhibitor, MK-8931, for Treatment of Alzheimer's Disease  |date=December 2012 }}</ref> In February 2017, Merck halted its late-stage trial of verubecestat for mild to moderate Alzheimer's disease after it was reported as having "virtually no chance" of working according to an independent panel of experts. This came just three months after Eli Lilly & Co. announced its own setback with [[solanezumab]]. The results of Merck's trial of verubecestat on patients with early stage Alzheimer's are still expected in February 2019.

In September 2014 [[AstraZeneca]] and [[Eli Lilly and Company]] announced an agreement to codevelop [[AZD3293]].<ref>{{cite web|url=http://www.astrazeneca.com/Media/Press-releases/Article/astrazeneca-and-lilly-announce-alliance | title=AstraZeneca and Lilly announce alliance to develop and commercialise BACE inhibitor AZD3293 for Alzheimer’s disease |date= 16 Sep 2014| accessdate= 8 Oct 2014 }}</ref> A pivotal Phase II/III clinical trial of [[AZD3293]] started in late 2014 and is planned to recruit 1,500 patients and end in May 2019.<ref>{{cite web |url=https://www.reuters.com/article/2014/12/01/health-alzheimers-astrazeneca-eli-lilly-idUSL6N0TL0ST20141201 |title=AstraZeneca and Lilly move Alzheimer's drug into big trial |date=December 2014 }}</ref>

===Potential side effects===
Tests in mice have indicated that BACE proteases, specifically BACE1, are necessary for the proper function of [[muscle spindle]]s.<ref>{{cite journal|last=Cheret|first=Cecil|author2=Michael Willem|author3=Florence R Fricker|author4=Hagen Wende|title=Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles|journal=European Molecular Biology Organization|date=June 2013|url=http://www.nature.com/emboj/journal/vaop/ncurrent/full/emboj2013146a.htmlnce }}</ref> These results raise the possibility that BACE inhibiting drugs currently being investigated for the treatment of Alzheimer's may have significant side effects related to impaired motor coordination,{{citation needed|date=February 2015}} though BACE1 [[Gene knockout|knockout]] mice are healthy.<ref>{{cite journal | vauthors = Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L | title = BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics | journal = Human Molecular Genetics | volume = 10 | issue = 12 | pages = 1317–24  | date = Jun 2001 | pmid = 11406613 | doi = 10.1093/hmg/10.12.1317 }}</ref>

== Relationship to plasmepsin ==

BACE1 is distantly related to the pathogenic aspartic-acid protease [[plasmepsin]], which is a potential target for future anti-malarial drugs.<ref name="pmid20130644">{{cite journal | vauthors = Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE | title = Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte | journal = Nature | volume = 463 | issue = 7281 | pages = 632–6 | date = Feb 2010 | pmid = 20130644 | pmc = 2826791 | doi = 10.1038/nature08726 | laysource = sciencedaily.com | layurl = http://www.sciencedaily.com/releases/2010/02/100203131405.htm | bibcode = 2010Natur.463..632R }}</ref>

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Hong L, He X, Huang X, Chang W, Tang J | title = Structural features of human memapsin 2 (beta-secretase) and their biological and pathological implications | journal = Acta Biochimica et Biophysica Sinica | volume = 36 | issue = 12 | pages = 787–92 | year = 2005 | pmid = 15592644 | doi = 10.1093/abbs/36.12.787 }}
* {{cite journal | vauthors = Johnston JA, Liu WW, Todd SA, Coulson DT, Murphy S, Irvine GB, Passmore AP | title = Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease | journal = Biochemical Society Transactions | volume = 33 | issue = Pt 5 | pages = 1096–100 | year = 2006 | pmid = 16246054 | doi = 10.1042/BST20051096 }}
* {{cite journal | vauthors = Dominguez DI, Hartmann D, De Strooper B | title = BACE1 and presenilin: two unusual aspartyl proteases involved in Alzheimer's disease | journal = Neuro-Degenerative Diseases | volume = 1 | issue = 4-5 | pages = 168–74 | year = 2006 | pmid = 16908986 | doi = 10.1159/000080982 }}
* {{cite journal | vauthors = Zacchetti D, Chieregatti E, Bettegazzi B, Mihailovich M, Sousa VL, Grohovaz F, Meldolesi J | title = BACE1 expression and activity: relevance in Alzheimer's disease | journal = Neuro-Degenerative Diseases | volume = 4 | issue = 2-3 | pages = 117–26 | year = 2007 | pmid = 17596706 | doi = 10.1159/000101836 }}
{{refend}}

== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=A01.004 A01.004]
* [http://www.rcsb.org/pdb/101/motm.do?momID=115 beta-Secretase: Molecule of the Month], by David Goodsell, RCSB Protein Data Bank
* {{UCSC gene info|BACE1}}

{{PDB Gallery|geneid=23621}}
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{{Aspartic acid proteases}}
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{{DEFAULTSORT:Beta Secretase}}
[[Category:Molecular neuroscience]]
[[Category:Integral membrane proteins]]
[[Category:EC 3.4.23]]
[[Category:Alzheimer's disease]]