Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model.
Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model.
复制标题
Caspase-1抑制减轻阿尔茨海默病小鼠模型的认知障碍和神经病理学。
DOI：
10.1038/s41467-018-06449-x
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发表时间：
2018-09-25
影响因子：
16.6
通讯作者：
LeBlanc AC
中科院分区：
文献类型：
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作者：
Flores J;Noël A;Foveau B;Lynham J;Lecrux C;LeBlanc AC
阿尔茨海默病(AD)是一种以认知功能减退和痴呆为特征的难治性进行性神经退行性疾病。涉及Caspase-1激活的炎性神经退行性变途径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，我们证明了无毒和血脑屏障通透性的小分子Caspase-1抑制剂VX-765剂量依赖地逆转了J20小鼠AD模型中的情景记忆和空间记忆障碍以及多动。停止VX-765治疗1个月后，小鼠的记忆障碍再次出现，重新开始治疗可恢复正常认知。VX-765可防止进行性淀粉样β蛋白沉积，逆转脑部炎症，并使小鼠海马区突触素蛋白水平正常化。与这些发现一致的是，Caspase-1基因缺失的J20小鼠可以免受间歇性和空间记忆缺陷、神经炎症和Aβ积聚的保护。这些结果为Caspase-1抑制AD认知缺陷和病理的体内概念提供了证据。Caspase-1在免疫细胞和人类中枢神经系统神经元中被应激激活，可能与神经元变性有关。在这里，作者研究了Caspase-1抑制剂在阿尔茨海默病小鼠模型中的治疗潜力。
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. Caspase-1, activated by stress in immune cells and in CNS human neurons, may contribute to neuronal degeneration. Here, the authors investigate the therapeutic potential of a Caspase-1 inhibitor in a mouse model of Alzheimer’s disease.