View source for Beta-secretase 1

{{Short description|Enzyme}}
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{{Infobox_gene}}
'''Beta-secretase 1''', also known as '''beta-site amyloid precursor protein cleaving enzyme 1''', '''beta-site APP cleaving enzyme 1''' ('''BACE1'''), '''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 = 735–741 | date = October 1999 | pmid = 10531052 | doi = 10.1126/science.286.5440.735 | url = https://escholarship.org/uc/item/7s76h7jk | access-date = 2019-07-01 | url-status = live | s2cid = 42481897 | archive-url = https://web.archive.org/web/20190409194738/https://escholarship.org/uc/item/7s76h7jk | archive-date = 2019-04-09 }}</ref> Expression of BACE1 is observed mainly in [[neuron]]s and [[oligodendrocyte]]s.<ref>{{cite journal | vauthors = Rajani RM, Ellingford R, Hellmuth M, Harris SS, Taso OS, Graykowski D, Lam FK, Arber C, Fertan E, Danial JS, Swire M, Lloyd M, Giovannucci TA, Bourdenx M, Klenerman D, Vassar R, Wray S, Sala Frigerio C, Busche MA | title = Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's disease | journal = PLOS Biology | volume = 22 | issue = 7 | pages = e3002727 | date = July 2024 | pmid = 39042667 | pmc = 11265669 | doi = 10.1371/journal.pbio.3002727 | doi-access = free }}</ref>

BACE1 is an [[aspartic acid protease]] important in the formation of [[myelin sheath]]s in peripheral nerve cells: in mice the expression of BACE1 is high in the postnatal stages, when [[myelination]] occurs.<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 = 664–666 | date = October 2006 | pmid = 16990514 | doi = 10.1126/science.1132341 | s2cid = 8432207 | bibcode = 2006Sci...314..664W }}
*{{lay source |template = cite magazine|vauthors = Phillips ML|url = https://www.the-scientist.com/daily-news/alzheimers-enzyme-important-for-myelin-47209|title = Alzheimer's enzyme important for myelin|date = September 21, 2006 |website = The Scientist }}</ref> The [[transmembrane protein]] contains two active site [[aspartate]] residues in its [[extracellular]] [[protein domain]] and may function as a [[protein dimer|dimer]], its cytoplasmic tail is required for the correct maturation and an efficient intracellular trafficking, but does not affect the activity. It is produced as a [[pro-enzyme]], the endoproteolitc removal occurs after BACE leaves [[endoplasmic reticulum]], in the [[Golgi apparatus]]. In addition the [[pro-peptide]] receives additional sugars to increase the molecular mass.<ref>{{cite journal | vauthors = Capell A, Steiner H, Willem M, Kaiser H, Meyer C, Walter J, Lammich S, Multhaup G, Haass C | title = Maturation and pro-peptide cleavage of beta-secretase | journal = The Journal of Biological Chemistry | volume = 275 | issue = 40 | pages = 30849–30854 | date = October 2000 | pmid = 10801872 | doi = 10.1074/jbc.M003202200 | doi-access = free }}</ref> and the tail became a [[palmitoylated]].{{citation needed|date=January 2024}}

The BACE1 expression is influenced by the inflammatory state: during [[Alzheimer's disease|AD]] the [[cytokine]]s reduce the [[Peroxisome proliferator-activated receptor|PPAR1]] an inhibitor of BACE1 mRNA.{{citation needed|date=January 2024}}

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

BACE1 is the major beta secretase for the generation of [[amyloid beta|amyloid-β]] [[peptides]] in the neurons.<ref>{{cite journal | vauthors = Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC | title = BACE1 is the major beta-secretase for generation of Abeta peptides by neurons | journal = Nature Neuroscience | volume = 4 | issue = 3 | pages = 233–234 | date = March 2001 | pmid = 11224536 | doi = 10.1038/85064 | s2cid = 11973104 }}</ref>

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, forming [[P3 peptide|P3]], this demonstrates that BACE1 and [[Alpha secretase]] compete for the APP processing.

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. [[BACE2]] is a close [[homology (biology)|homolog]] of BACE1 with no reported APP cleavage ''in vivo''.

The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown: some studies observed that BACE1 is involved in [[myelination]] (it is co-express with [[neuregulin 1]] type III). In a manner analogous to APP processing, the [[Sodium channel|VGSC]] subunit beta is a substrate for BACE1.<ref>{{cite journal | vauthors = Kim DY, Carey BW, Wang H, Ingano LA, Binshtok AM, Wertz MH, Pettingell WH, He P, Lee VM, Woolf CJ, Kovacs DM | title = BACE1 regulates voltage-gated sodium channels and neuronal activity | journal = Nature Cell Biology | volume = 9 | issue = 7 | pages = 755–764 | date = July 2007 | pmid = 17576410 | pmc = 2747787 | doi = 10.1038/ncb1602 }}</ref>

However a single residue mutation in APP reduces the ability of BACE1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimer's disease 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 |access-date=2012-07-16 |archive-date=2012-05-15 |archive-url=https://web.archive.org/web/20120515014627/http://pennstatehershey.adam.com/content.aspx?productId=16 |url-status=live }}</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 = 96–99 | date = August 2012 | pmid = 22801501 | doi = 10.1038/nature11283 | s2cid = 4333449 | 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 Alzheimer's disease.<ref>{{cite journal | vauthors = Pradeepkiran JA, Reddy AP, Yin X, Manczak M, Reddy PH | title = Protective effects of BACE1 inhibitory ligand molecules against amyloid beta-induced synaptic and mitochondrial toxicities in Alzheimer's disease | journal = Human Molecular Genetics | volume = 29 | issue = 1 | pages = 49–69 | date = January 2020 | pmid = 31595293 | pmc = 7001603 | doi = 10.1093/hmg/ddz227 }}</ref>

===For Alzheimer's 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 = 332–335 | date = July 2006 | pmid = 16644763 | doi = 10.1093/ageing/afl009 | doi-access =  }}</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 = 4261–4264 | date = September 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 |access-date=2012-07-16 |archive-date=2013-09-26 |archive-url=https://web.archive.org/web/20130926070344/http://www.alzforum.org/new/detail.asp?id=1790 |url-status=live }}</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 |url-status=dead |archive-url=https://web.archive.org/web/20120728084446/http://www.merck.com/newsroom/news-release-archive/research-and-development/2012_0427.html |archive-date=2012-07-28 }}</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 |access-date=2012-12-13 |archive-date=2017-02-27 |archive-url=https://web.archive.org/web/20170227090142/http://www.mercknewsroom.com/press-release/research-and-development-news/merck-initiates-phase-iiiii-study-investigational-bace-i |url-status=dead }}</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]]. 

In September 2014 [[AstraZeneca]] and [[Eli Lilly and Company]] announced an agreement to codevelop [[lanabecestat]] (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 |access-date=8 Oct 2014 |archive-date=23 September 2015 |archive-url=https://web.archive.org/web/20150923175656/http://www.astrazeneca.com/Media/Press-releases/Article/astrazeneca-and-lilly-announce-alliance |url-status=live }}</ref> A pivotal Phase II/III clinical trial of lanabecestat started in late 2014,<ref>{{cite news |url=https://www.reuters.com/article/health-alzheimers-astrazeneca-eli-lilly-idUSL6N0TL0ST20141201 |title=AstraZeneca and Lilly move Alzheimer's drug into big trial |date=December 2014 |newspaper=Reuters |access-date=2017-06-30 |archive-date=2015-10-25 |archive-url=https://web.archive.org/web/20151025091302/http://www.reuters.com/article/2014/12/01/health-alzheimers-astrazeneca-eli-lilly-idUSL6N0TL0ST20141201 |url-status=live }}</ref> but was halted in 2018 before its planned conclusion due to poor results.<ref>{{cite web |url= https://www.astrazeneca.com/media-centre/press-releases/2018/update-on-phase-iii-clinical-trials-of-lanabecestat-for-alzheimers-disease-12062018.html |title= Update on Phase III Clinical Trials of lanabecestat |date= 12 June 2018 |access-date= 20 June 2018 |archive-date= 5 June 2022 |archive-url= https://web.archive.org/web/20220605033230/https://www.astrazeneca.com/media-centre/press-releases/2018/update-on-phase-iii-clinical-trials-of-lanabecestat-for-alzheimers-disease-12062018.html |url-status= live }}</ref>

Another BACE1 inhibitor that has reached phase II trials is the Eli Lilly's inhibitor LY2886721. The data on phase I trial were first presented at the Alzheimer's Association International conference in 2012. Daily dosing during 2 weeks, reduced BACE1 activity by 50–75% and CSF Aβ42 by 72% (Willis et al., 2012; Bowman Rogers and Strobel, 2013). Recently, Lilly reported that the phase II trial of LY2886721 was terminated due to liver abnormalities that were found in 4 out of 45 patients (Rogers, 2013). This toxicity, however, does not have to be related to the working mechanism of the inhibitor, but can represent off-target effects as the livers of BACE1 knockout mice are normal.

===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 | vauthors = Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, Tahirovic S, Nave KA, Saftig P, Haass C, Garratt AN, Bennett DL, Birchmeier C | title = Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles | journal = The EMBO Journal | volume = 32 | issue = 14 | pages = 2015–2028 | date = July 2013 | pmid = 23792428 | pmc = 3715864 | doi = 10.1038/emboj.2013.146 }}</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,<ref>{{cite journal | vauthors = Pettersson AF, Olsson E, Wahlund LO | title = Motor function in subjects with mild cognitive impairment and early Alzheimer's disease | journal = Dementia and Geriatric Cognitive Disorders | volume = 19 | issue = 5–6 | pages = 299–304 | date = 2005 | pmid = 15785030 | doi = 10.1159/000084555 | s2cid = 36382718 }}</ref> 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 = 1317–1324 | date = June 2001 | pmid = 11406613 | doi = 10.1093/hmg/10.12.1317 | doi-access = free }}</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 | bibcode = 2010Natur.463..632R }}
*{{lay source |template = cite press release|url = https://www.sciencedaily.com/releases/2010/02/100203131405.htm|title = Scientists find ideal target for malaria therapy|date = February 4, 2010 |website = ScienceDaily }}</ref>

== References ==
{{reflist|30em}}

== Further reading ==
{{refbegin|30em}}
* {{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 = 787–792 | 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 | s2cid = 44248549 | 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 | s2cid = 26746944 | doi-access =  }}
* {{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 | s2cid = 32898359 }}
{{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] {{Webarchive|url=https://web.archive.org/web/20121121090414/http://www.rcsb.org/pdb/101/motm.do?momID=115 |date=2012-11-21 }}, by David Goodsell, RCSB Protein Data Bank
* {{UCSC gene info|BACE1}}
* {{PDBe-KB2|P56817|Human Beta-secretase 1}}

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