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 BACE1gene.[5] Expression of BACE1 is observed mainly in neurons and oligodendrocytes.[6]
The BACE1 expression is influenced by the inflammatory state: during AD the cytokines reduce the PPAR1 an inhibitor of BACE1 mRNA.[citation needed]
Role in Alzheimer's disease
Processing of the amyloid precursor protein
BACE1 is the major beta secretase for the generation of amyloid-βpeptides in the neurons.[9]
Generation of the 40 or 42 amino acid-long amyloid-βpeptides 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 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, 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 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 VGSC subunit beta is a substrate for BACE1.[10]
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.[11][12]
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.[13]
For Alzheimer's disease
Several companies are in the early stages of development and testing of this potential class of treatment.[14][15] In March 2008 phase I results were reported for CoMentis Inc's candidate CTS-21166.[16]
In April 2012 Merck & Co., Inc reported phase I results for its candidate verubecestat (MK-8931).[17] Merck began a Phase II/III trial of MK-8931 in December, 2012 estimated to be completed in July 2019.[18] 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).[19] A pivotal Phase II/III clinical trial of lanabecestat started in late 2014,[20] but was halted in 2018 before its planned conclusion due to poor results.[21]
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 spindles.[22] 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,[23] though BACE1 knockout mice are healthy.[24]
Relationship to plasmepsin
BACE1 is distantly related to the pathogenic aspartic-acid protease plasmepsin, which is a potential target for future anti-malarial drugs.[25]
^Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, et al. (March 2001). "BACE1 is the major beta-secretase for generation of Abeta peptides by neurons". Nature Neuroscience. 4 (3): 233–234. doi:10.1038/85064. PMID11224536. S2CID11973104.
^Walker LC, Rosen RF (July 2006). "Alzheimer therapeutics-what after the cholinesterase inhibitors?". Age and Ageing. 35 (4): 332–335. doi:10.1093/ageing/afl009. PMID16644763.
^Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL, et al. (September 2007). "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 of Medicinal Chemistry. 50 (18): 4261–4264. doi:10.1021/jm0705408. PMID17685503.
^Pettersson AF, Olsson E, Wahlund LO (2005). "Motor function in subjects with mild cognitive impairment and early Alzheimer's disease". Dementia and Geriatric Cognitive Disorders. 19 (5–6): 299–304. doi:10.1159/000084555. PMID15785030. S2CID36382718.
Hong L, He X, Huang X, Chang W, Tang J (2005). "Structural features of human memapsin 2 (beta-secretase) and their biological and pathological implications". Acta Biochimica et Biophysica Sinica. 36 (12): 787–792. doi:10.1093/abbs/36.12.787. PMID15592644.
Johnston JA, Liu WW, Todd SA, Coulson DT, Murphy S, Irvine GB, et al. (2006). "Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease". Biochemical Society Transactions. 33 (Pt 5): 1096–100. doi:10.1042/BST20051096. PMID16246054. S2CID44248549.
Dominguez DI, Hartmann D, De Strooper B (2006). "BACE1 and presenilin: two unusual aspartyl proteases involved in Alzheimer's disease". Neuro-Degenerative Diseases. 1 (4–5): 168–74. doi:10.1159/000080982. PMID16908986. S2CID26746944.
Zacchetti D, Chieregatti E, Bettegazzi B, Mihailovich M, Sousa VL, Grohovaz F, et al. (2007). "BACE1 expression and activity: relevance in Alzheimer's disease". Neuro-Degenerative Diseases. 4 (2–3): 117–26. doi:10.1159/000101836. PMID17596706. S2CID32898359.
External links
The MEROPS online database for peptidases and their inhibitors: A01.004
