摘要
促使淀粉样前体蛋白(APP)裂解成淀粉样蛋白β(Aβ)肽的β分泌酶BACE1是阿尔茨海默氏病(AD)的一个主要的治疗靶点。但是,最近使用基因动物模型所获得的研究引发了我们的担忧,临床上BACE1抑制剂面临着病情恶化的过程中改善AD样病理和记忆障碍的药效显著降低的情况。在这里,我们比较强效的选择性小分子抑制剂BACE1 GRL-8234对不同病理阶段的AD小鼠模型的影响。具体而言,我们给5XFAD转基因小鼠注射GRL-8234(33.4毫克/千克,i.p.),每日一次,持续2个月,这显示出适度的(4个月)和大量(10月龄)Aβ斑块沉积的起点。用GRL-8234慢性治疗逆转了记忆损伤:在自发交替Y-迷宫任务实验中,年轻5XFAD小鼠出现脑Aβ42水平显著减少。与此相反,在给予GRL-8234的12个月大的5XFAD小鼠可观察到,Aβ42的只出现轻微的降低,记忆功能仍然受损。我们发现,随着Aβ在5XFAD小鼠内积聚,BACE1和全长的APP表达都显著升高,而GRL-8234未能改善这些有害机制,从而进一步加速老年5XFAD小鼠大脑斑块的生长。因此,我们的研究结果提供了对AD的发展过程中Aβ积累和BACE1抑制所引起相关的无法治愈记忆障碍的重要见解。
关键词: 5XFAD,阿耳茨海默氏病,淀粉样蛋白β,APP,BACE1抑制剂,C99 GRL-8234,学习和记忆。
Current Alzheimer Research
Title:Beneficial Effects of the β-Secretase Inhibitor GRL-8234 in 5XFAD Alzheimer’s Transgenic Mice Lessen During Disease Progression
Volume: 12 Issue: 1
Author(s): Latha Devi, Jordan Tang and Masuo Ohno
Affiliation:
关键词: 5XFAD,阿耳茨海默氏病,淀粉样蛋白β,APP,BACE1抑制剂,C99 GRL-8234,学习和记忆。
摘要: The β-secretase enzyme BACE1, which initiates the cleavage of amyloid precursor protein (APP) into the amyloid-β (Aβ) 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) Aβ 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 Aβ42 levels. In contrast, only marginal reductions of Aβ42 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 Aβ 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 Aβ accumulation and related memory impairments become less responsive to rescue by BACE1 inhibition during the course of AD development.
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Devi Latha, Tang Jordan and Ohno Masuo, Beneficial Effects of the β-Secretase Inhibitor GRL-8234 in 5XFAD Alzheimer’s Transgenic Mice Lessen During Disease Progression, Current Alzheimer Research 2015; 12 (1) . https://dx.doi.org/10.2174/1567205012666141218125042
DOI https://dx.doi.org/10.2174/1567205012666141218125042 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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