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

摘要 根据最近的估计，近600万美国人患有阿尔茨海默病(AD)，导致 估计医疗成本为2900亿美元。随着人口老龄化，这些数字预计将 随着时间的推移大幅增加。尽管阿尔茨海默病传统上被认为是一种仅影响 神经元，对血管成分的欣赏越来越多；AD患者经常表现出 脑血管改变和高血压等心血管疾病的经典危险因素 与痴呆症和阿尔茨海默病风险增加独立相关。尽管确切的机制 这些观察结果背后的原因还不完全清楚，这两种疾病都被证明会影响血管系统 导致脑血流量改变和血脑屏障(BBB)退化。 在这项申请中提出的研究的目标是检验高血压作用于 与AD相关病理协同作用增强内皮功能障碍和随后的血脑屏障 退化。为了测试这一点，我们将评估内皮细胞(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，并与这些改变相关 阿尔茨海默病相关淀粉样变性发生发展过程中脑血流和血脑屏障通透性的变化 和高血压，无论是作为单独的实体还是组合在一起。这些研究的结果将导致更好的 了解脑血管系统早期病理变化的分子机制。 此外，这些数据可能导致确定早期(临床前)靶点，以供未来研究评估 它们作为潜在的(基于血液的)生物标记物或作为治疗干预的靶标的应用。尤其是 对于AD，由于目前没有治愈和治疗选择，主要集中在减少或控制 症状，能够在临床前阶段识别疾病将使早期干预成为可能，因此 增加治疗成功的概率。

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.