Abstract
BACE1 was discovered as the β-secretase for initiating the cleavage of amyloid precursor protein (APP) at the β-secretase site, while its close homology BACE2 cleaves APP within the β-amyloid (Aβ) domain region and shows distinct cleavage preferences in vivo. Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and thus specific inhibition of BACE1 by small molecules is a current focus for Alzheimer’s disease therapy. While BACE1 inhibitors are being tested in advanced clinical trials, knowledge regarding the properties and physiological functions of BACE is highly important and this review summarizes advancements in BACE1 research over the past several years. We and others have shown that BACE1 is not only a critical enzyme for testing the “Amyloid Hypothesis” associated with Alzheimer’s pathogenesis, but also important for various functions such as axon growth and pathfinding, astrogenesis, neurogenesis, hyperexcitation, and synaptic plasticity. BACE2 appears to play different roles such as glucose homeostasis and pigmentation. This knowledge regarding BACE1 functions is critical for monitoring the safe use of BACE1 inhibitors in humans.
Highlights
Riqiang Yan*Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and specific inhibition of BACE1 by small molecules is a current focus for Alzheimer’s disease therapy
For over 30 years, the study of β-amyloid (Aβ) peptides has been the largest field of research geared toward understanding Alzheimer’s pathogenesis and therapeutic intervention
Inhibition of BACE1 is one the most promising therapeutic targets for treating Alzheimer’s disease (AD), and five drugs have currently entered into clinical trials (Vassar, 2014; Yan, 2016)
Summary
Inhibition of BACE1 proteolytic activity has been confirmed to decrease Aβ generation and amyloid deposition, and specific inhibition of BACE1 by small molecules is a current focus for Alzheimer’s disease therapy. While BACE1 inhibitors are being tested in advanced clinical trials, knowledge regarding the properties and physiological functions of BACE is highly important and this review summarizes advancements in BACE1 research over the past several years. We and others have shown that BACE1 is a critical enzyme for testing the “Amyloid Hypothesis” associated with Alzheimer’s pathogenesis, and important for various functions such as axon growth and pathfinding, astrogenesis, neurogenesis, hyperexcitation, and synaptic plasticity. BACE2 appears to play different roles such as glucose homeostasis and pigmentation. This knowledge regarding BACE1 functions is critical for monitoring the safe use of BACE1 inhibitors in humans
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