Ischemic Stroke in Cerebral Amyloid Angiopathy: Microvascular Injury and Recovery

脑淀粉样血管病中的缺血性中风：微血管损伤和恢复

• 批准号: 10537550
• 负责人: Olivia Marlowe Colbert
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537550
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Architecture; Autopsy; Basal Ganglia; Bioenergetics; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain region; Bromodeoxyuridine; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrovascular system; Clinical; Coagulation Process; Complex; Cues; Dementia; Deposition; Diagnosis; Differentiation Antigens; Dyes; Extravasation; Functional disorder; Future; Gene Expression; Genus Hippocampus; Health; Hippocampus (Brain); Hospitals; Hour; Human; Immunohistochemistry; Impaired cognition; Infarction; Inflammasome; Inflammatory; Inflammatory Response; Interruption; Ischemia; Ischemic Stroke; Lead; Learning; Measures; Mediating; Medicine; Mitochondria; Monitor; Motor; Mus; Neurologic; Neuronal Dysfunction; Neurons; Neuropathogenesis; Outcome; Pathway interactions; Patients; Permeability; Proliferating; Proteins; Recovery; Rehabilitation therapy; Research; Risk Factors; Sampling; Severities; Signal Transduction; Sodium Fluorescein; Stains; Stroke; Therapeutic; Tight Junctions; Tissues; Transgenic Organisms; Vascular Diseases; Western Blotting; abeta accumulation; age related; behavior test; blood-brain barrier disruption; brain tissue; burden of illness; cerebral microvasculature; cerebrovascular; chemokine; clinical practice; clinically relevant; cognitive function; endothelial dysfunction; experimental study; gene complementation; injury recovery; insight; intercellular communication; memory process; mitochondrial dysfunction; mitochondrial metabolism; mouse model; negative affect; nerve stem cell; nervous system disorder; neurogenesis; neurological rehabilitation; neuron development; neuropathology; normal aging; post stroke; protein expression; stem cells; stroke outcome; stroke recovery; stroke survivor; targeted treatment; trafficking; translational medicine

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.

项目摘要 缺血性卒中后的恢复是脑卒中后最关键的康复医学问题之一， 药虽然目前的治疗方法在清除血栓方面是有效的，但大多数患者不会去医院 在大脑发生严重组织损伤之前，多达三分之二的中风幸存者 需要神经康复此外，卒中后结局在患者中的研究很少 脑淀粉样血管病（CAA）CAA是脑血管疾病的一种形式，其特征在于 脑血管系统（包括血脑屏障）内大量β-淀粉样蛋白（Aβ）蓄积 （BBB）。这种情况超过了与正常衰老相关的淀粉样蛋白沉积，并可能导致与年龄相关的 神经功能衰退此外，CAA中Aβ积聚是缺血性梗死和降解的危险因素 血管壁的结构。血管壁结构的完整性对于中风后组织恢复至关重要，因为 许多增殖的神经前体细胞（NPC）与脑血管系统（BBB）紧密相连并与之相通。 这种可被中风耗尽的增殖性NPC库可受到Aβ积累的相互影响， 导致运动和认知功能的延迟恢复。我们的目标是了解背后的机制 延迟中风后恢复，因为这两个条件，使有针对性的治疗，可以提出在 未来 为了研究这一点，我们将采用一种转基因5xFAD小鼠模型，该模型重现了Aβ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，Aβ蓄积在 脑血管通过诱导血脑屏障加重缺血性卒中结局并延迟卒中后恢复 NPC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。虽然没有有效的策略， 治疗缺血性卒中后的组织损伤和/或治疗脑中的Aβ积聚，该项目的重点是 探讨CAA相关性卒中的发病机制，为今后的治疗策略提供参考。限定 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意义 和临床实践，因为大多数被诊断患有阿尔茨海默病（AD）的患者也存在 CAA;因此，CAA引起的大部分疾病负担可能与临床相关， AD.