Beta-secretase 1, also known asbeta-site amyloid precursor protein cleaving enzyme 1,beta-site APP cleaving enzyme 1 (BACE1),membrane-associated aspartic protease 2,memapsin-2,aspartyl protease 2, andASP2, is anenzyme that in humans is encoded by theBACE1gene.[5] Expression of BACE1 is observed mainly inneurons andoligodendrocytes.[6]
BACE1 is anaspartic acid protease important in the formation ofmyelin sheaths in peripheral nerve cells: in mice the expression of BACE1 is high in the postnatal stages, whenmyelination occurs.[7] Thetransmembrane protein contains two active siteaspartate residues in itsextracellularprotein domain and may function as adimer, its cytoplasmic tail is required for the correct maturation and an efficient intracellular trafficking, but does not affect the activity. It is produced as apro-enzyme, the endoproteolitc removal occurs after BACE leavesendoplasmic reticulum, in theGolgi apparatus. In addition thepro-peptide receives additional sugars to increase the molecular mass.[8] and the tail became apalmitoylated.[citation needed]
The BACE1 expression is influenced by the inflammatory state: duringAD thecytokines reduce thePPAR1 an inhibitor of BACE1 mRNA.[citation needed]
BACE1 is the major beta secretase for the generation ofamyloid-βpeptides in neurons.[9]
Generation of the 40 or 42amino acid-longamyloid-βpeptides that aggregate in thebrain of Alzheimer's patients requires two sequential cleavages of theamyloid 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 byγ-secretase releases the intracellular domain of APP and produces amyloid-β. Sincegamma-secretase cleaves APP closer to thecell 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, formingP3, this demonstrates that BACE1 andAlpha secretase compete for the APP processing.
Unlike APP and thepresenilin proteins important in γ-secretase, no knownmutations in thegene 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 closehomolog of BACE1 with no reported APP cleavagein vivo.
The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown: some studies observed that BACE1 is involved inmyelination (it is co-express withneuregulin 1 type III). In a manner analogous to APP processing, theVGSC 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]
Drugs to block this enzyme (BACE inhibitors) in theory would prevent the buildup of beta-amyloid and (per theAmyloid hypothesis) may help slow or stop Alzheimer's disease.[13]
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 2012Merck & Co., Inc reported phase I results for its candidateverubecestat (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 withsolanezumab.
In September 2014AstraZeneca andEli Lilly and Company announced an agreement to codeveloplanabecestat (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.
Tests in mice have indicated that BACE proteases, specifically BACE1, are necessary for the proper function ofmuscle 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 BACE1knockout mice are healthy.[24]
BACE1 is distantly related to the pathogenic aspartic-acid proteaseplasmepsin, which is a potential target for future anti-malarial drugs.[25]
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