Alzheimer's disease (AD) is an intractable progressive neurodegenerative disease characterized by cognitive decline and dementia. An inflammatory neurodegenerative pathway, involving Caspase-1 activation, is associated with human age-dependent cognitive impairment and several classical AD brain pathologies. Here, we show that the nontoxic and blood-brain barrier permeable small molecule Caspase-1 inhibitor VX-765 dose-dependently reverses episodic and spatial memory impairment, and hyperactivity in the J20 mouse model of AD. Cessation of VX-765 results in the reappearance of memory deficits in the mice after 1 month and recommencement of treatment re-establishes normal cognition. VX-765 prevents progressive amyloid beta peptide deposition, reverses brain inflammation, and normalizes synaptophysin protein levels in mouse hippocampus. Consistent with these findings, Caspase-1 null J20 mice are protected from episodic and spatial memory deficits, neuroinflammation and Aβ accumulation. These results provide in vivo proof of concept for Caspase-1 inhibition against AD cognitive deficits and pathologies.

中文翻译：

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Caspase-1 抑制可减轻阿尔茨海默病小鼠模型中的认知障碍和神经病理学。

阿尔茨海默病（AD）是一种以认知能力下降和痴呆为特征的顽固性进行性神经退行性疾病。涉及 Caspase-1 激活的炎症性神经退行性通路与人类年龄依赖性认知障碍和几种经典的 AD 脑病理有关。在这里，我们展示了无毒且可渗透血脑屏障的小分子 Caspase-1 抑制剂 VX-765 剂量依赖性地逆转 AD J20 小鼠模型中的情节和空间记忆障碍以及多动症。停止使用 VX-765 会导致 1 个月后小鼠再次出现记忆缺陷，并且重新开始治疗可重新建立正常认知。VX-765 可防止进行性β淀粉样肽沉积，逆转脑部炎症，并使小鼠海马中的突触素蛋白水平正常化。与这些发现一致，Caspase-1 缺失的 J20 小鼠受到保护，免于发作性和空间记忆缺陷、神经炎症和 Aβ 积累。这些结果为 Caspase-1 抑制 AD 认知缺陷和病理提供了体内概念证明。