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

基本信息

批准号：
10555225
负责人：
Rachel Elise Bennett
金额：
$ 41.81万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10555225
关键词：
3-Dimensional Affect Age Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animals Automobile Driving Biological Biological Markers Blood Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Blood capillaries Blood flow Brain Brain region Cell Aging Cells Cerebrovascular Circulation Cerebrovascular system Cognition 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 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 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 genetic manipulation human data human imaging human old age (65+)human tissue imaging study innovation insight mild cognitive impairment molecular marker mouse model neuroimaging neuron loss novel overexpression patient population prevent reconstruction regional difference resilience senescence spatial relationship stressor targeted treatment tau Proteins therapeutic gene tool transcriptome transcriptomics vascular inflammation vascular risk factor vascular stress

项目摘要

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）和认知障碍的一个关键特征。这种功能障碍的原因在很大程度上尚不清楚，但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。阿尔茨海默病研究中心 (ADRC) 和小鼠模型来检验在目标 1 中，我们将确定微血管应激出现的时间和地点。在目标 2 中，我们将确定微血管是否与β淀粉样斑块和缠结的积累有关。通过测量一组数据，压力会导致 AD 中血脑屏障 (BBB) 的功能减弱血清蛋白并通过显微解剖“渗漏”和“非渗漏”血管来确定其机制基础在目标 3 中，我们将操纵单个血管片段水平的基因表达。内皮细胞并测试特定微血管应激源对 AD 病理变化的因果作用。这项工作将评估阿尔茨海默病患者多个大脑区域的人类血管转录组，提供关于血管细胞如何受 AD 病理影响的无与伦比的信息以及对血管细胞变异性的洞察人类大脑血管系统可能是疾病易感性区域差异的基础。利用包括多重免疫荧光在内的创新方法来测量多达 18 种蛋白质立即进行组织切片，清除大脑准备，以评估压力标记和压力标记之间的空间关系 AD 病理学，以及一种可以特异性靶向脉管系统中内皮细胞的新型腺相关病毒总的来说，这可能是未来治疗基因传递的一个令人兴奋的工具。有助于我们了解 AD 中微血管功能受损的生物学机制，并将帮助发现生物标志物，以确定可从血管定向治疗中受益的患者群体由这个项目产生的。