期刊
CURRENT ALZHEIMER RESEARCH
卷 12, 期 1, 页码 13-21出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205012666141218125042
关键词
5XFAD; Alzheimer's disease; amyloid-beta; APP; BACE1 inhibitor; C99; GRL-8234; learning and memory
资金
- Alzheimer's Art Quilt Initiative Grant
- National Institutes of Health [AG044703]
The beta-secretase enzyme BACE1, which initiates the cleavage of amyloid precursor protein (APP) into the amyloid-beta (A beta) peptide, is a prime therapeutic target for Alzheimer's disease (AD). However, recent investigations using genetic animal models raise concern that therapeutic BACE1 inhibition may encounter the dramatic reduction of efficacy in ameliorating AD-like pathology and memory deficits during disease progression. Here, we compared the effects of the potent and selective small-molecule BACE1 inhibitor GRL-8234 in different pathological stages of AD mouse model. Specifically, we administered GRL-8234 (33.4 mg/kg, i.p.) once daily for 2 months to 5XFAD transgenic mice, which showed modest (4 months) and massive (10 months of age) A beta plaque deposition at starting points. Chronic treatments with GRL-8234 reversed memory impairments, as tested by the spontaneous alternation Y-maze task, in the younger 5XFAD group concomitant with significant reductions in cerebral A beta 42 levels. In contrast, only marginal reductions of A beta 42 were observed in 12-month-old 5XFAD mice treated with GRL-8234 and their memory function remained impaired. We found that not only BACE1 but also full-length APP expression was significantly elevated with progressive A beta accumulation in 5XFAD mice, while GRL-8234 failed to affect these detrimental mechanisms that further accelerate plaque growth in brains of older 5XFAD mice. Therefore, our results provide important insights into the mechanisms by which A beta accumulation and related memory impairments become less responsive to rescue by BACE1 inhibition during the course of AD development.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据