Microvascular Stress as a Pathway to Neurodegeneration in Alzheimer's

微血管应激是阿尔茨海默氏症神经退行性病变的途径

• 批准号: 10361894
• 负责人: Rachel Elise Bennett
• 金额: $ 39.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361894
• 关键词: 3-Dimensional; Affect; Age; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animals; Automobile Driving; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain region; Cell Aging; Cells; Cerebrovascular Circulation; Cerebrovascular system; Cognitive; Data; Dependovirus; Deposition; Disease; Disease susceptibility; Endothelial Cells; Epitopes; Experimental Models; Extravasation; Functional disorder; Future; Gene Delivery; Gene Expression; Genes; Heterogeneity; Histologic; Histology; Human; Hypertension; Immunofluorescence Immunologic; Impaired cognition; Impairment; Individual; Inflammation; Knowledge; Lasers; Lesion; Link; Massachusetts; Measures; Mediating; Mediator of activation protein; Medical; Methods; Microvascular Dysfunction; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathologic; Pathology; Pathway interactions; Persons; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Preparation; Process; Proteins; RNA; Reporting; Research; Risk Factors; Role; SERPINE1 gene; Sampling; Senile Plaques; Serum Proteins; Severities; Specificity; Stress; Sum; Techniques; Testing; Therapeutic; Tissue Sample; Tissues; Transgenic Mice; Up-Regulation; Vascular Endothelium; Work; abeta accumulation; angiogenesis; blood-brain barrier function; blood-brain barrier permeabilization; cardiovascular disorder risk; cerebral microvasculature; functional disability; human data; human imaging; human old age (65+); human tissue; imaging study; innovation; insight; molecular marker; mouse model; neuroimaging; neuron loss; novel; patient population; prevent; reconstruction; regional difference; senescence; spatial relationship; stressor; targeted treatment; tau Proteins; therapeutic gene; tool; transcriptome; transcriptomics; vascular inflammation; vascular risk factor; vascular stress

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.

项目摘要 影响血流和血脑屏障功能的脑微血管系统的变化越来越多 被认为是早期阿尔茨海默病（AD）和认知障碍的关键特征。底层 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， 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τ沉积。这项研究将利用在马萨诸塞州收集的人体组织样本 阿尔茨海默氏病研究中心（ADRC）和小鼠模型，以研究 微血管应激与AD的关系在目标1中，我们将确定微血管应力出现的时间和位置， 与β淀粉样蛋白斑块和缠结的积累有关。在目标2中，我们将确定微血管 通过测量一组AD患者的血脑屏障（BBB）， 血清蛋白，并通过显微解剖“渗漏”和“非渗漏”血管，以确定 单个血管节段水平的功能障碍。在目标3中，我们将操纵基因表达， 内皮细胞和测试的因果关系的作用，具体的微血管应激病理性AD的变化。这 这项工作将评估来自阿尔茨海默氏症多个大脑区域的人类血管转录组， 关于血管细胞如何受到AD病理学影响的无与伦比的信息，以及对 人类大脑血管系统可能是疾病易感性区域差异的基础。此外，我们将 利用创新的方法，包括多重免疫荧光，测量多达18种蛋白质， 组织切片，清晰的大脑准备，以评估压力标志物和 AD病理学和一种可特异性靶向血管内皮细胞的新型腺相关病毒 这可能是未来治疗基因传递的一个令人兴奋的工具。总的来说，这些研究将大大 有助于我们了解AD微血管功能受损的生物学机制， 帮助发现生物标志物，以识别将从血管导向治疗中受益的患者群体 从这个项目中产生的。