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Journal Articles Biological Psychiatry Year : 2021

The β-Secretase BACE1 in Alzheimer’s Disease

Massimo Corbo
  • Function : Author
Michael Irizarry
  • Function : Author
Bruce Albala
  • Function : Author
Akihiko Koyama
  • Function : Author
Naoto Watanabe
  • Function : Author
Teiji Kimura
  • Function : Author
Lisa Yarenis
  • Function : Author
Lynn Kramer
  • Function : Author

Abstract

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-β (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, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aβ production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with 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 pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as 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 enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.
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hal-03197728 , version 1 (24-04-2023)

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Attribution - NonCommercial

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Harald Hampel, Robert Vassar, Bart de Strooper, John Hardy, Michael Willem, et al.. The β-Secretase BACE1 in Alzheimer’s Disease. Biological Psychiatry, 2021, 89 (8), pp.745-756. ⟨10.1016/j.biopsych.2020.02.001⟩. ⟨hal-03197728⟩
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