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Development and use of amyloid secretase modulators in Alzhaimer's disease.

淀粉样蛋白分泌酶调节剂在阿尔茨海默病中的开发和应用。

基本信息

批准号：
13210027
负责人：
ISHIURA Shoichi
金额：
$ 41.73万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

项目摘要

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid β peptide (Aβ), is generated from amyloid precursor protein (APP) by β-and γ. secretase-mediated cleavages. Since BACE1 (β-site APP cleaving enzyme 1)-knockout mice produce much less Aβand grow healthily without apparent side effects, BACE1 inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD.Here, we report in vivo inhibitory effects of a novel BACE1 inhibitor, KMI-429, which is a transition-state mimic, effectively inhibits β- secretase activity in cultured cells in a dose-dependent manner. We injected KMI.429 into the hippocampus of APP transgenic and wild-type mice and measured the release of sAPPβ (soluble extracellular fragment of APP generated by β-secretase), the level of APP-CTF (C-terminal fragment of APP) and Aβ level by quantitative Western blotting and sandwitch ELISA. KMI.429 significantly reduced Aβ production in soluble fraction compared with vehicle in vivo, but changes in Aβ levels in insoluble fraction were not so affected. In contrast, the intrahippocampal injection of KMI.429 in wild-type mice remarkably reduced Aβ production in both soluble and insoluble fractions. Our results indicate that the BACE1 inhibitor KMI.429 would be a promising candidate for a treatment for AD.

阿尔茨海默病（AD）是一种神经退行性疾病，其特征是大脑中淀粉样斑块和神经原纤维缠结的积累。斑块的主要成分β淀粉样肽（Aβ）是由淀粉样前体蛋白（APP）通过β-和γ产生的。分泌酶介导的切割。由于 BACE1（β 位点 APP 裂解酶 1）敲除小鼠产生的 Aβ 少得多，并且健康生长且无明显副作用，因此 BACE1 抑制剂被认为是开发 AD 治疗干预措施中最具吸引力的靶标之一。在这里，我们报告了一种新型 BACE1 抑制剂 KMI-429 的体内抑制作用，KMI-429 是一种过渡态模拟物，可有效抑制培养细胞中的β-分泌酶活性呈剂量依赖性。我们将KMI.429注射到APP转基因和野生型小鼠的海马中，并通过定量Western blotting和夹心ELISA测量sAPPβ（β分泌酶产生的APP的可溶性胞外片段）的释放、APP-CTF（APP的C端片段）的水平和Aβ水平。与体内载体相比，KMI.429 显着降低可溶性级分中的 Aβ 产量，但不溶性级分中 Aβ 水平的变化并未受到太大影响。相比之下，在野生型小鼠的海马内注射 KMI.429 显着降低了可溶性和不溶性组分中 Aβ 的产生。我们的结果表明 BACE1 抑制剂 KMI.429 将成为治疗 AD 的有希望的候选药物。