Latrepirdine (Dimebon®) 是一种潜在的阿尔茨海默氏症治疗剂，可调节阿尔茨海默病小鼠模型中的自噬和神经病理学。,Autophagy

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Latrepirdine (Dimebon®) 是一种潜在的阿尔茨海默氏症治疗剂，可调节阿尔茨海默病小鼠模型中的自噬和神经病理学。
Autophagy ( IF 14.6 ) Pub Date : 2013-02-06 , DOI: 10.4161/auto.23487
John W Steele ₁ , Sam Gandy

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阿尔茨海默病 (AD) 是一种神经退行性疾病，它在数十年的过程中发展，并且是致病性淀粉样蛋白 β (Aβ) 肽（也称为 A4）积累的结果。在晚期 AD 中，自噬清除失败导致神经元细胞体几乎完全被自噬泡 (AVs) 消耗。此前，我们已经证明潜在的 AD 药物拉曲吡定（又名 Dimebon(®)），一种俄罗斯抗组胺药，在 AD 的 II 期临床试验中显示出不同的结果，调节淀粉样蛋白-β/A4 前体蛋白 (APP) 的代谢。在 2012 年的两篇分子精神病学论文中，我们试图确定拉曲匹定调节 APP 代谢的机制，并使用阿尔茨海默病小鼠模型确定，latrepirdine 是否提供保护免受与 Aβ 积累相关的毒性。在培养的细胞中，我们提供了证据表明拉曲匹定刺激 MTOR 和 ATG5 依赖性自噬，导致细胞内 APP 代谢物（包括 Aβ）水平降低。与这一发现一致，我们发现长期服用拉曲匹定导致被认为与 TgCRND8（APP K670M、N671L、V717F）或野生型小鼠大脑中自噬激活相关的生物标志物水平升高，并且该治疗与废除有关TgCRND8 小鼠的行为缺陷、Aβ 神经病理学减少和自噬衰竭的预防。导致 APP 代谢物（包括 Aβ）的细胞内水平降低。与这一发现一致，我们发现长期服用拉曲匹定导致被认为与 TgCRND8（APP K670M、N671L、V717F）或野生型小鼠大脑中自噬激活相关的生物标志物水平升高，并且该治疗与废除有关TgCRND8 小鼠的行为缺陷、Aβ 神经病理学减少和自噬衰竭的预防。导致 APP 代谢物（包括 Aβ）的细胞内水平降低。与这一发现一致，我们发现长期服用拉曲匹定导致被认为与 TgCRND8（APP K670M、N671L、V717F）或野生型小鼠大脑中自噬激活相关的生物标志物水平升高，并且该治疗与废除有关TgCRND8 小鼠的行为缺陷、Aβ 神经病理学减少和自噬衰竭的预防。

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Latrepirdine (Dimebon®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model.

Alzheimer disease (AD) is a form of neurodegeneration that develops over the course of multiple decades and as a result of the accumulation of the pathogenic amyloid-β (Aβ) peptide, also known as A4. In late-stage AD, failure of autophagic clearance results in neuronal cell bodies that are almost entirely consumed by autophagic vacuoles (AVs). Previously, we have shown that the potential AD drug latrepirdine (aka Dimebon(®)), a Russian antihistamine that has shown mixed results in phase II clinical trials in AD, regulates metabolism of the amyloid-β/A4 precursor protein (APP). In two Molecular Psychiatry papers in 2012, we sought to determine the mechanism through which latrepirdine regulates APP metabolism and to determine, using an Alzheimer mouse model, whether latrepirdine provides protection from the toxicity associated with the accumulation of Aβ. In cultured cells, we provided evidence that latrepirdine stimulates MTOR- and ATG5-dependent autophagy, leading to the reduction of intracellular levels of APP metabolites, including Aβ. Consistent with this finding, we found that chronic latrepirdine administration resulted in increased levels of the biomarkers thought to correlate with autophagy activation in the brains of TgCRND8 (APP K670M, N671L, V717F) or wild-type mice, and that treatment was associated with abrogation of behavioral deficit, reduction in Aβ neuropathology, and prevention of autophagic failure among TgCRND8 mice.

更新日期：2013-02-04

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