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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease.
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A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease.

机译：一种非竞争性BACE1抑制剂TAK-070可改善阿尔茨海默氏病小鼠模型中的Abeta病理学和行为缺陷。

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摘要

We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.
机译：我们发现了一种非肽化合物TAK-070，它以非竞争性方式抑制BACE1，这是一种限速蛋白酶，可导致Abeta肽的生成，而Abeta肽被认为是导致阿尔茨海默氏病（AD）的原因。 TAK-070与全长BACE1结合，但与缺乏跨膜结构域的截短BACE1结合。短期口服TAK-070可降低大脑中可溶性Abe​​ta的水平，将神经营养性sAPPalpha的水平提高约20％，并使Tg2576小鼠（AD的APP转基因小鼠模型）的认知测试中的行为障碍正常化。六个月的长期治疗使大脑Abeta沉积降低了约60％，从而保留了对可溶性Abe​​ta和sAPPalpha水平的药理作用。这些结果支持用非竞争性抑制剂抑制BACE1作为疾病改善和对症治疗的可行性。

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