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

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聚。斑块的主要成分淀粉样蛋白β肽(Aβ)由淀粉样前体蛋白(APP)由β-和γ产生。分泌酶介导的卵裂。由于BACE1(β-Site APP裂解酶1)基因敲除小鼠产生的Aβ少得多，而且生长健康，没有明显的副作用，BACE1抑制剂被认为是开发AD治疗干预措施的最具吸引力的靶点之一。将KMI.429注射到APP转基因小鼠和野生型小鼠的海马区，用定量Western blotting和双抗体夹心法检测APPβ(β分泌酶产生的可溶性APP胞外片段)、APP-CTF(APP C末端片段)和Aβ的水平。与赋形剂相比，KMI.429显著降低了可溶性组分中Aβ的产生，但对不溶性组分中Aβ水平的变化影响不大。相比之下，在野生型小鼠的海马区注射KMI.429显著减少了可溶和不可溶部分Aβ的产生。我们的结果表明，BACE1抑制剂KMI.429将是治疗AD的一个有前途的候选药物。

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 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.