Ischemic Stroke in Cerebral Amyloid Angiopathy: Microvascular Injury and Recovery

项目摘要 缺血性中风后的康复是最关键的康复医学问题之一 医药。虽然目前的治疗方法在清除血栓方面是有效的，但大多数患者并不去医院就诊。 在大脑中发生严重的组织损伤之前，多达三分之二的中风幸存者 需要神经康复。此外，中风后的预后在患者中的研究也很少。 患有脑淀粉样血管病(CAA)。CAA是脑血管疾病的一种，其特点是 β-淀粉样蛋白(A-β)在脑血管系统，包括血脑屏障中大量积聚 (Bbb)。这种情况超过了与正常衰老相关的淀粉样蛋白沉积，并可能导致年龄相关 神经功能衰退。此外，Aβ在CAA中的积聚是缺血性梗塞和退化的危险因素 脉管壁的建筑。血管壁结构的完整性对卒中后组织恢复至关重要，因为 许多增殖性神经前体细胞(NPC)靠近脑血管系统(BBB)并与之沟通。 这种可能因中风而枯竭的增殖性鼻咽癌细胞池可能会受到β积聚的相互影响， 导致运动和认知功能恢复延迟。我们的目标是了解背后的机制 由于这两种情况导致卒中后恢复延迟，因此可以在 未来。 为了研究这一点，我们将使用一个转基因的5xFAD小鼠模型，它概括了β在大脑中的积累 分析CAA与脑血管缺血的关系。这项研究的中心假设是β在体内的积累 脑血管系统通过诱导血脑屏障加重缺血性卒中结局并延缓卒中后恢复 神经前体细胞的功能障碍和异常神经发生。实验也将集中在中风后的神经发生上。 作为微血管功能和诱导它的生物能量机制。虽然没有有效的战略来 治疗缺血性中风后的组织损伤和/或治疗脑内β积聚，该项目重点 探讨CAA相关卒中的发病机制，为今后制定治疗策略提供参考。定义 CAA和缺血性卒中事件的神经发病机制在转化医学中具有重要的相关性 和临床实践，因为大多数被诊断为阿尔茨海默病(AD)的患者还存在 CAA；因此，CAA造成的大多数疾病负担在临床上可能与治疗有关，这些治疗也影响 广告。

Project Summary Recovery after ischemic stroke is one of the most critical rehabilitative medical problems in medicine. While current treatments are effective in removing clots, most patients do not present to hospitals before serious tissue damage occurs in the brain, with as many as two-thirds of stroke survivors requiring neurorehabilitation. Furthermore, post-stroke outcomes have been poorly studied in patients with cerebral amyloid angiopathy (CAA). CAA is a form of cerebrovascular disease and is characterized by substantial beta-amyloid (Aβ) accumulation within cerebral vasculature, including the blood-brain barrier (BBB). This condition exceeds amyloid deposits associated with normal aging and may contribute to age-related neurological decline. Additionally, Aβ accumulation in CAA is a risk factor for ischemic infarcts and degradation of vessel wall architecture. The integrity of vessel wall architecture is crucial for post-stroke tissue recovery since many proliferative neural progenitor cells (NPC) are close to and communicating with cerebral vasculature (BBB). This pool of proliferative NPCs that can become depleted by stroke can be mutually affected by Aβ accumulation, leading to delayed recovery of both motor and cognitive functions. We aim to understand the mechanism behind delayed post-stroke recovery because of both conditions so that targeted therapies can be proposed in the future. To study this, we will employ a transgenic 5xFAD mouse model that recapitulates Aβ accumulation in the brain to analyze CAA and cerebrovascular ischemia. The central hypothesis of this study is that Aβ accumulation in cerebral vasculature exacerbates ischemic stroke outcomes and delays post-stroke recovery by inducing BBB dysfunction and aberrant neurogenesis of NPCs. Experiments will focus on neurogenesis post-stroke, as well as microvascular function and the bioenergetic mechanisms that induce it. While there is no effective strategy to treat tissue damage following ischemic stroke and/or treat Aβ accumulation in the brain, this project focuses on the mechanism of CAA-related stroke in order to develop therapeutic strategies in the future. Defining neuropathogenesis of both CAA and ischemic stroke incidents is of significant relevance in translational medicine and clinical practice because most patients diagnosed with Alzheimer’s Disease (AD) also present with CAA; therefore, most of the disease burden due to CAA can be clinically relevant to treatments that also affect AD.