The β-secretase BACE1 in Alzheimer’s disease

2020 
Abstract The β-site amyloid precursor protein cleaving enzyme 1 (BACE1), was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of Aβ, including Aβ42, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer’s disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thus supporting the hypothesis that BACE1 may drive AD progression. Therefore, BACE1 is a prime drug target for slowing down Aβ production in early AD. Besides the amyloidgenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and homeostasis. Indeed, germline and adult conditional BACE1-knockout mice display complex neurological phenotypes. All BACE1 inhibitor clinical trials conducted so far were discontinued for futility or safety reasons. Despite these negative results, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with a high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aβ and BACE1 in physiological processes and key disease mechanisms of AD. The functions of BACE1 and the homologue BACE2 and the biology of Aβ in neurons and glia deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important aspartic proteases and identifying their substrates. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.
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