There are no approved symptomatic treatments for vascular dementia (VaD). Rapamycin (RAPA) improves cognitive deficits in Alzheimer’s disease rats. To explore whether RAPA improves cognitive impairment after VaD and its possible molecular mechanisms. Thirty Sprague Dawley rats were randomly divided into three groups: sham (received sham-operation), VaD model (received permanent ligation of bilateral carotid arteries) and RAPA (7.5 mg/kg) treatment. Cognitive function was evaluated by Morris water maze test. Neuronal apoptosis was evaluated by TUNEL staining. Mitophagy was assessed by mitochondrial DNA (mtDNA), ATP level, transmission electron microscope and mitophagy-associated proteins. Proteins were quantified by Western blot and immunofluorescence. BV2 cells were exposed to RAPA or/and MHY1485 (mTOR activator) to verify in vivo results. Compared to VaD rats, the escape latency of RAPA-treated rats was significantly decreased, and time spent in target quadrant was longer. Pathologic changes, mitochondrial dysfunction, increase of neuronal apoptosis and related proteins in VaD rats were remarkably alleviated by RAPA. After RAPA treatment, an increase in number of autophagosomes was observed, along with up-regulation of mitophagy-related proteins. Overexpression of PI3K, AKT and mTOR were suppressed by RAPA treatment. In vitro experiments confirmed effects of RAPA, and demonstrated that MHY1485 addition reversed the RAPA-caused apoptosis inhibition and mitophagy enhancement. Overall, RAPA improved the cognitive impairment of VaD rats, alleviated neuronal injury and mitochondrial dysfunction. We proposed a potential mechanism that RAPA may play improving role by inhibiting neuronal apoptosis and enhancing mitophagy through PI3K/AKT/mTOR pathway. Findings provided an exciting possibility for novel treatment strategy of VaD.

目前尚无批准的针对血管性痴呆 (VaD) 的对症治疗方法。雷帕霉素 (RAPA) 可改善阿尔茨海默病大鼠的认知缺陷。探讨RAPA是否能改善VaD后的认知障碍及其可能的分子机制。将30只Sprague Dawley大鼠随机分为三组：假手术组（接受假手术）、VaD模型组（接受双侧颈动脉永久结扎）和RAPA（7.5 mg/kg）治疗。通过Morris水迷宫测试评估认知功能。通过TUNEL染色评估神经元凋亡。通过线粒体 DNA (mtDNA)、ATP 水平、透射电子显微镜和线粒体自噬相关蛋白来评估线粒体自噬。通过蛋白质印迹和免疫荧光对蛋白质进行定量。将 BV2 细胞暴露于 RAPA 或/和 MHY1485（mTOR 激活剂）以验证体内结果。与VaD大鼠相比，RAPA治疗组大鼠的逃避潜伏期显着缩短，并且在目标象限中停留的时间更长。 RAPA可显着减轻VaD大鼠的病理变化、线粒体功能障碍、神经元凋亡和相关蛋白的增加。 RAPA 处理后，观察到自噬体数量增加，同时线粒体自噬相关蛋白上调。 RAPA 处理抑制了 PI3K、AKT 和 mTOR 的过度表达。体外实验证实了 RAPA 的作用，并证明添加 MHY1485 可逆转 RAPA 引起的细胞凋亡抑制和线粒体自噬增强。总体而言，RAPA 改善了 VaD 大鼠的认知障碍，减轻了神经元损伤和线粒体功能障碍。我们提出了一个潜在的机制，即RAPA可能通过PI3K/AKT/mTOR通路抑制神经元凋亡和增强线粒体自噬来发挥改善作用。 研究结果为 VaD 的新治疗策略提供了令人兴奋的可能性。