Journal
BIOLOGICAL PSYCHIATRY
Volume 89, Issue 8, Pages 745-756Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2020.02.001
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Funding
- Phoenix program by the Sorbonne University Foundation
- AXA Research Fund
- Fondation partenariale Sorbonne Universite
- Fondation pour la Recherche sur Alzheimer
- Investissements d'avenir program [ANR-10-IAIHU-06]
- Fondazione Turano
- Pfizer
- Avid
- MSD Avenir
- Functional Neuromodulation
- Axovant
- Eli Lilly
- Takeda
- Zinfandel
- GE Healthcare
- Oryzon Genomics
- MRC [MR/N026004/1, UKDRI-1009, G0901254, UKDRI-1004, G0701075] Funding Source: UKRI
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BACE1 is a well-validated therapeutic target for slowing down Aβ production in early AD, despite previous clinical trials being discontinued. Further research should focus on the roles of BACE1 and Aβ in physiological and pathophysiological processes, as well as the substrates and downstream effects of BACE1 and BACE2.
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-f3 (Af3), including Af342, 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 Af3 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 Af3 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 Af3 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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