Contribution of Endothelial Changes and Increased Cardiovascular Risk to Alzheimer's Disease Pathogenesis

内皮变化和心血管风险增加对阿尔茨海默病发病机制的贡献

• 批准号: 10302662
• 负责人: Audrey Cleuren
• 金额: --
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302662
• 关键词: Affect; Affinity Chromatography; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease risk; American; Amyloid beta-Protein; Animals; Appearance; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Cardiovascular Diseases; Cells; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Clinical; Complex Mixtures; Data; Disease; Early Intervention; Early identification; Endothelial Cells; Endothelium; Environment; Evaluation; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Goals; Health Care Costs; Hippocampus (Brain); Hypertension; Impaired cognition; Label; Laser Speckle Imaging; Link; Measures; Messenger RNA; Molecular; Molecular Weight; Neurofibrillary Tangles; Neurons; Organ; Outcome Measure; Pathogenesis; Pathologic; Pathology; Patients; Perfusion; Play; Population; Probability; Resolution; Ribosomes; Role; Senile Plaques; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Tracer; Transcript; Translating; Visualization; amyloidogenesis; blood perfusion; blood-based biomarker; blood-brain barrier permeabilization; cardiovascular risk factor; cell type; cerebrovascular; clinically relevant; dementia risk; endothelial dysfunction; in vivo; in vivo evaluation; insight; mouse model; neurovascular unit; pre-clinical; programs; single-cell RNA sequencing; success; targeted treatment; transcriptome sequencing; treatment group; vascular factor; virtual

ABSTRACT According to recent estimates, close to 6 million Americans are living with Alzheimer’s disease (AD), leading to an estimated health cost of $290 billion. With the aging of the population, these numbers are expected to substantially increase over time. Although AD has traditionally been considered to be a disease affecting only neurons, there is an increasing appreciation for a vascular component; patients with AD often display cerebrovascular alterations, and classical risk factors for cardiovascular diseases such as hypertension, have been independently associated with an increased risk for dementia and AD. Although the exact mechanisms underlying these observations are not fully understood, both disorders have been shown to affect the vasculature leading to alterations in cerebral blood flow and degradation of the blood-brain barrier (BBB). The goal of the studies proposed in this application is to test the hypothesis that high blood pressure acts in a synergistic manner with AD-related pathology to augment endothelial dysfunction and subsequent BBB degradation. To test this, we will evaluate changes in endothelial cell (EC) gene expression programs using an in vivo EC-specific translating ribosome affinity purification (TRAP) approach, and correlate these to alterations in cerebral blood flow and BBB permeability during the onset and progression of AD-related amyloidogenesis and hypertension, either as separate entities or combined. The results of these studies will lead to a better understanding of the molecular mechanisms underlying the early pathologic changes in the cerebrovasculature. In addition, these data may result in the identification of early (preclinical) targets for future studies to assess their application as a potential (blood-based) biomarker or as a target for therapeutic interventions. Particularly for AD, as there is currently no cure and treatment options are mostly focused on reducing or controlling symptoms, being able to identify the disorder in the preclinical stage would enable an early intervention and thus increase the probability of therapeutic success.

抽象的 根据最近的估计，近600万美国人患有阿尔茨海默氏病（AD），导致 估计健康成本为2900亿美元。随着人口的衰老，这些数字有望 随着时间的流逝，广告大幅增加。尽管传统上被认为是一种影响的疾病 神经元，对血管成分的欣赏越来越多。广告患者经常显示 脑血管改变以及心血管疾病（例如高血压）的经典危险因素具有 我们与痴呆症和AD的风险增加了独立联系。虽然确切的机制 基础这些观察结果尚不完全了解，两种疾病都已证明会影响脉管系统 导致脑血流的改变和血脑屏障（BBB）的降解。 本应用中提出的研究的目的是检验以下假设：高血压在A中起作用 与广告相关病理学的协同方式，以增强内皮功能障碍和随后的BBB 降解。为了测试这一点，我们将使用A的内皮细胞（EC）基因表达程序的变化使用 体内EC特异性翻译核糖体亲和力纯化（TRAP）方法，并将其与变化相关联 在脑血流和BBB渗透性中，与广告相关的淀粉样生成的发作和进展 和高血压，要么是独立的实体，要么合并。这些研究的结果将导致更好 理解脑血管造期早期病理变化的分子机制。 此外，这些数据可能导致鉴定以后研究的早期（临床前）目标 它们用作潜在的（基于血液）生物标志物或治疗干预措施的靶标。特别 对于广告 症状，能够在临床前阶段鉴定该疾病将使早期干预，从而可以 增加热成功的可能性。