It is estimated that up to 1 in 3 healthy middle-aged adults will have had a covert stroke during their lifetime. Furthermore, post-stroke, survivors are more than twice as likely to develop dementia. In the present study, we aimed to model the impact of focal subclinical ischemia prior to the onset of AD pathogenesis in a preclinical model. We utilized endothelin-1 to induce ischemia in an iducible transgenic mouse model of Alzheimer’s disease, APPsi:tTA, allowing for temporal control of APP gene expression. We induced the focal subclinical ischemic events in the absence of APP expression, thus prior to AD onset. T2 structural magnetic resonance imaging confirmed the volume and location of focal subclinical ischemic lesions to the medial prefrontal cortex. Following recovery from surgery and 7 weeks of APP expression, we found that two subclinical ischemic lesions resulted in a significant localized increase in amyloid load and in microglial activation proximal to the lesion. However, no differences were found in astrogliosis. A battery of behaviour tests was conducted, in which no significant differences were detected in activities of daily living and cognitive function between stroked and sham cohorts. Overall, our results demonstrated that APP expression was the sole driving force behind behavioural deficits. In conclusion, our results suggest that a history of two subclinical strokes prior to AD onset does not worsen early disease trajectory in a mouse model.

据估计，多达三分之一的健康中年人会在其一生中隐匿中风。此外，中风后，幸存者患痴呆症的可能性是其两倍多。在本研究中，我们旨在在临床前模型中模拟 AD 发病机制开始前局灶性亚临床缺血的影响。我们利用内皮素-1 在可诱导的阿尔茨海默病转基因小鼠模型 APPsi:tTA 中诱导缺血，允许对 APP 基因表达进行时间控制。我们在没有 APP 表达的情况下诱导了局灶性亚临床缺血事件，因此在 AD 发作之前。T2 结构磁共振成像证实了内侧前额叶皮层的局灶性亚临床缺血性病变的体积和位置。在手术恢复和 APP 表达 7 周后，我们发现两个亚临床缺血性病变导致淀粉样蛋白负荷和病变近端小胶质细胞激活的显着局部增加。然而，在星形胶质细胞增生中没有发现差异。进行了一系列行为测试，其中在日常生活活动和认知功能方面未检测到中风组和假组之间的显着差异。总的来说，我们的结果表明 APP 表达是行为缺陷背后的唯一驱动力。总之，我们的结果表明，在小鼠模型中，AD 发病前两次亚临床中风的病史不会恶化早期疾病轨迹。进行了一系列行为测试，其中在日常生活活动和认知功能方面未检测到中风组和假组之间的显着差异。总的来说，我们的结果表明 APP 表达是行为缺陷背后的唯一驱动力。总之，我们的结果表明，在小鼠模型中，AD 发病前两次亚临床中风的病史不会恶化早期疾病轨迹。进行了一系列行为测试，其中在日常生活活动和认知功能方面未检测到中风组和假组之间的显着差异。总的来说，我们的结果表明 APP 表达是行为缺陷背后的唯一驱动力。总之，我们的结果表明，在小鼠模型中，AD 发病前两次亚临床中风的病史不会恶化早期疾病轨迹。