Microvascular Stress as a Pathway to Neurodegeneration in Alzheimer's

项目摘要 影响血流和血脑屏障功能的脑微血管改变越来越多 被认为是早期阿尔茨海默病(AD)和认知障碍的关键特征。潜在的 这种功能障碍的原因在很大程度上是未知的，尽管来自转基因小鼠的数据表明与 微血管应激(炎症、衰老和血管生成)随着淀粉样蛋白的增加而上调 β和tau沉积。这项研究将利用在马萨诸塞州收集的人类组织样本 阿尔茨海默病研究中心(ADRC)和小鼠模型，以检查贡献 微血管应激对AD的影响。在目标1中，我们将确定微血管应激出现的时间和地点 与淀粉样β斑块和缠结堆积的关系。在目标2中，我们将确定微血管 应激通过测量一组血脑屏障(BBB)的 通过显微解剖“渗漏”和“非渗漏”血管以确定其发病机制。 单个血管节段水平上的功能障碍。在目标3中，我们将在 并检测特定微血管应激源对AD病理性改变的致病作用。这 这项工作将评估阿尔茨海默病患者多个脑区的人类血管转录本，提供 关于血管细胞如何受到AD病理影响的无与伦比的信息，以及对 人类脑血管结构可能是疾病易感性地区差异的基础。此外，我们还将 利用包括多重免疫荧光在内的创新方法测量多达18种蛋白质 一次组织切片，清除大脑准备，以评估应激标志物和 AD病理，以及一种新型的腺相关病毒，它可以特异性地靶向血管系统中的内皮细胞 这可能是未来治疗性基因传递的一个令人兴奋的工具。总体而言，这些研究将显著 有助于我们了解AD微血管功能受损的生物学机制 帮助发现生物标记物，以确定将受益于血管导向疗法的患者群体 从这个项目中产生。

Project Abstract Changes to cerebral microvasculature that impact blood flow and blood brain barrier function are increasingly recognized as a key feature of early Alzheimer’s disease (AD) and cognitive impairment. The underlying cause of this dysfunction is largely unknown, though data from transgenic mice indicates pathways related to microvascular stress (inflammation, senescence, and angiogenesis) are upregulated with increasing amyloid beta and tau deposition. This research will make use of human tissue samples collected in the Massachusetts Alzheimer’s Disease Research Center (ADRC) and mouse models to examine the contribution of microvascular stress to AD. In Aim 1, we will determine when and where microvascular stress appears in relation to accumulation of amyloid beta plaques and tangles. In Aim 2, we will determine if microvascular stress contributes to functional weakening of the blood brain barrier (BBB) in AD by measuring a panel of serum proteins and by microdissecting “leaky” and “non-leaky” vessels to identify a mechanistic basis for dysfunction at the level of individual vessel segments. In Aim 3 we will manipulate gene expression in endothelial cells and test the causal role of specific microvascular stressors to pathological AD changes. This work will assess human vascular transcriptomes from multiple brain regions in Alzheimer’s, providing unparalleled information about how vascular cells are affected by AD pathology and insight into variability of human brain vasculature that might underlie regional differences in disease susceptibility. Further, we will make use of innovative methods including multiplex immunofluorescence to measure up to 18 proteins in tissue sections at once, clear brain preparations to assess spatial relationships between stress markers and AD pathology, and a novel adeno-associated virus that can specifically target endothelial cells in vasculature and that may be an exciting tool for future therapeutic gene delivery. Overall, these studies will significantly contribute to our knowledge of the biological mechanisms of impaired microvascular function in AD and will help uncover biomarkers to identify patient populations that would benefit from vascular-directed therapeutics arising from this project.