Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada.
Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada.
Neuroscience. 2022 Apr 1;487:47-65. doi: 10.1016/j.neuroscience.2022.01.026. Epub 2022 Feb 3.
Ischemic stroke often co-occurs with Alzheimer's disease (AD) leading to a worsened clinical outcome. Neuroinflammation is a critical process implicated in AD and ischemic pathology, associated with cognitive decline. We sought to investigate the combined effects of ischemic stroke induced by endothelin-1 injection in two AD rat models, using motor function, memory and microglial inflammation in the basal forebrain and striatum as readouts. In addition, we sought to determine the effectiveness of the antioxidant biologic CAT-SKL in one of the models. The early AD model employed the bilateral intracerebroventricular injections of the toxic β-amyloid peptide Aβ, the prodromal AD model used the transgenic Fischer 344 rat overexpressing a pathological mutant human amyloid precursor protein. Motor function was assessed using a cylinder, modified sticky tape and beam-walk tasks; learning and memory were tested in the Morris water maze. Microglial activation was examined using immunohistochemistry. Aβ toxicity and stroke combination greatly increased microglial inflammation in the basal forebrain. Prodromal AD-pathology coupled with ischemia in the transgenic rat resulted in a greater microgliosis in the striatum. Combined transgenic rats showed balance alterations, comorbid Aβ rats showed a transient sensorimotor deficit, and both demonstrated spatial reference memory deficit. CAT-SKL treatment ameliorated memory impairment and basal forebrain microgliosis in Aβ rats with stroke. Our results suggest that neuroinflammation could be one of the early processes underlying the interaction of AD with stroke and contributing to the cognitive impairment, and that therapies such as antioxidant CAT-SKL could be a potential therapeutic strategy.
缺血性中风常与阿尔茨海默病（AD）同时发生，导致临床预后恶化。神经炎症是 AD 和缺血性病理中一个关键过程，与认知能力下降有关。我们试图通过检测基底前脑和纹状体中的运动功能、记忆和小胶质细胞炎症来研究内皮素-1 注射诱导的缺血性中风对两种 AD 大鼠模型的综合影响。此外，我们还试图确定抗氧化生物 CAT-SKL 在其中一种模型中的有效性。早期 AD 模型采用双侧脑室内注射有毒的β-淀粉样肽 Aβ，前驱 AD 模型采用过表达病理性突变人淀粉样前体蛋白的 Fischer 344 转基因大鼠。运动功能通过圆筒、改良胶带和梁行走任务进行评估；学习和记忆在 Morris 水迷宫中进行测试。使用免疫组织化学检测小胶质细胞激活。Aβ 毒性和中风的组合大大增加了基底前脑的小胶质细胞炎症。转基因大鼠的前驱 AD 病理与缺血相结合，导致纹状体中的小胶质细胞增生更多。联合转基因大鼠表现出平衡改变，合并 Aβ 的大鼠表现出短暂的感觉运动缺陷，两者均表现出空间参考记忆缺陷。CAT-SKL 治疗改善了 Aβ 大鼠中风后的记忆障碍和基底前脑小胶质细胞炎症。我们的结果表明，神经炎症可能是 AD 与中风相互作用的早期过程之一，并导致认知障碍，而抗氧化 CAT-SKL 等治疗方法可能是一种潜在的治疗策略。
