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Alzheimer's therapy targeting the β-secretase enzyme BACE1: Benefits and potential limitations from the perspective of animal model studies.

Abstract：

:Accumulating evidence points to the amyloid-β (Aβ) peptide as the culprit in the pathogenesis of Alzheimer's disease (AD). β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a protease that is responsible for initiating Aβ production. Although precise mechanisms that trigger Aβ accumulation remain unclear, BACE1 inhibition undoubtedly represents an important intervention that may prevent and/or cure AD. Remarkably, animal model studies with knockouts, virus-delivered small interfering RNAs, immunization and bioavailable small-molecule agents that specifically inhibit BACE1 activity strongly support the idea for the therapeutic BACE1 inhibition. Meanwhile, a growing number of BACE1 substrates besides APP uncover new physiological roles of this protease, raising some concern regarding the safety of BACE1 inhibition. Here, I review recent progress in preclinical studies that have evaluated the efficacies and potential limitations of genetic/pharmacological inhibition of BACE1, with special focus on AD-associated phenotypes including synaptic dysfunction, neuron loss and memory deficits in animal models.

journal_name

Brain Res Bull

journal_title

Brain research bulletin

authors

Ohno M

doi

10.1016/j.brainresbull.2016.04.007

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

183-198

issue

Pt 2

eissn

0361-9230

issn

1873-2747

pii

S0361-9230(16)30081-8

journal_volume

126

pub_type

杂志文章,评审

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