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病 (AD)，导致 随着人口老龄化，这些数字预计将增加 2,900 亿美元。 尽管 AD 传统上被认为是一种仅影响的疾病。 神经元中，AD 患者经常表现出对血管成分的日益重视； 脑血管改变以及高血压等心血管疾病的典型危险因素 尽管确切的机制与痴呆和阿尔茨海默病的风险增加独立相关。 这些观察结果的基础尚不完全清楚，这两种疾病已被证明会影响脉管系统 导致脑血流改变和血脑屏障（BBB）退化。 本申请中提出的研究的目的是检验高血压在以下方面起作用的假设： 与 AD 相关病理学协同作用，增强内皮功能障碍和随后的血脑屏障 为了测试这一点，我们将使用一个评估内皮细胞（EC）基因表达程序的变化。 体内 EC 特异性翻译核糖体亲和纯化 (TRAP) 方法，并将这些方法与改变相关联 AD 相关淀粉样变发生和进展过程中脑血流量和 BBB 通透性的变化 和高血压，无论是作为单独的实体还是结合起来，这些研究的结果都会带来更好的结果。 了解脑血管系统早期病理变化的分子机制。 此外，这些数据可能会导致确定早期（临床前）目标，以供未来研究评估 它们作为潜在的（基于血液的）生物标志物或作为治疗干预的目标的应用。 对于 AD，目前尚无治愈方法，治疗方案主要集中于减少或控制 症状，能够在临床前阶段识别疾病将有助于早期干预，从而 增加治疗成功的可能性。