The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice
The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice
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DOI：
10.1111/j.1471-4159.2005.03576.x
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发表时间：
2006-01-01
影响因子：
4.7
通讯作者：
Ishiura, S
中科院分区：
文献类型：
--
作者：
Asai, M;Hattori, C;Ishiura, S
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分泌酶介导的裂解产生的。由于 β-分泌酶/β-位点 APP 裂解酶 1 (BACE1) 敲除小鼠产生的 Aβ 量少得多且生长正常，因此 β-分泌酶抑制剂被认为是开发 AD 治疗干预措施最有吸引力的靶标之一，而且没有明显的副作用。在这里，我们报告了一种新型 β 分泌酶抑制剂 KMI-429（一种过渡态模拟物）的体内抑制作用，它以剂量依赖性方式有效抑制培养细胞中的 β 分泌酶活性。我们将 KMI-429 注射到 APP 转基因小鼠的海马体中。与媒介物相比，KMI-429 显着降低体内可溶性级分中的 Aβ 产生，但不溶性级分中的 Aβ 水平不受影响。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部分中 Aβ 的产生。我们的结果表明，β-分泌酶抑制剂 KMI-429 是治疗 AD 的有希望的候选药物。
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 beta peptide (A beta), is generated from amyloid precursor protein (APP) by beta- and gamma-secretase-mediated cleavage. Because beta-secretase/beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less A beta and grow normally, a beta-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects. Here, we report the in vivo inhibitory effects of a novel beta-secretase inhibitor, KMI-429, a transition-state mimic, which effectively inhibits beta-secretase activity in cultured cells in a dose-dependent manner. We injected KMI-429 into the hippocampus of APP transgenic mice. KMI-429 significantly reduced A beta production in vivo in the soluble fraction compared with vehicle, but the level of A beta in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wild-type mice remarkably reduced A beta production in both the soluble and insoluble fractions. Our results indicate that the beta-secretase inhibitor KMI-429 is a promising candidate for the treatment of AD.