Flores Joseph, Noël Anastasia, Foveau Bénédicte, Beauchet Olivier, LeBlanc Andréa C
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Nat Commun. 2020 Sep 11;11(1):4571. doi: 10.1038/s41467-020-18405-9.
Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APP) J20 and wild-type mice with VX-765 delays both APP- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.
早期治疗干预对于预防阿尔茨海默病（AD）至关重要。几种炎症相关基因标记与AD的关联以及AD中促炎途径的早期激活表明炎症是一个合理的治疗靶点。炎性半胱天冬酶-1对AD样病理生理有重大影响，半胱天冬酶-1抑制剂VX-765可逆转AD小鼠模型中的认知缺陷。在此，用VX-765对瑞典/印第安纳突变淀粉样前体蛋白（APP）J20小鼠和野生型小鼠进行为期一个月的症状前治疗，可延缓APP诱导和年龄诱导的情景记忆和空间记忆缺陷。VX-765可延缓炎症，而对可溶性和聚集性淀粉样β肽（Aβ）水平影响不大。情景记忆评分与小胶质细胞激活呈负相关。这些结果表明，半胱天冬酶-1介导的炎症在疾病早期就会发生，并带来了希望，即VX-765（一种先前已获美国食品药品监督管理局批准用于人体中枢神经系统临床试验的药物）可能是预防AD认知缺陷和脑部炎症发作的有用药物。
