Neurodegeneration and Microvascular Damage in Alzheimer's Disease

项目总结/摘要 AD和血管性痴呆传统上被认为是单独的病理;然而，最近的数据显示， 提示脑血管损伤和AD病理学对 认知功能脑血管改变对AD发病和进展的作用是一个重要的研究领域。 研究领域。对人类尸检大脑的研究表明，脑血管疾病的严重程度 与痴呆症相关，最常见的痴呆症归因于AD。然而，根本的机制不是 清楚地了解，脑血管损伤是否是AD发病机制的因果因素， AD进展的后果尚不清楚。了解AD发病机制之间的相互作用 脑血管损伤的发病机制可能导致新疗法的发展， 两个目标。然而，只有在过去的十年里，我们才知道同样的信号分子，例如， VEGF和BDNF影响神经元和血管网络的生长。PKCε激活mRNA- 稳定蛋白Hu，其增强VEGF和BDNF的表达。PKCε的减少发生在神经元 和血管内皮细胞在老年人，AD，和缺血性脑。我们假设AD病理结果 神经系统和心血管系统的综合因素在目标1中，我们将在神经元中发病， 在人类AD和年龄匹配的对照组中， 高血压、心脏病和/或脑血管疾病。这将提供一个全面的了解， 发病机制与神经元相关的MV结构变化。在目标2中，我们将评估PKCε 脑血管病和非脑血管病AD转基因小鼠模型早期空间记忆缺陷的激活 疾病基于我们以前的结果，我们期望表明脑血管疾病和MV变化 加速神经元丢失和AD发病机制，这受到PKCε增强的VEGF和BDNF的保护 表情在目的3中，我们将确定PKCε激活对早期空间记忆缺陷的影响， AD合并高血压性心脏病的转基因小鼠模型。在这个目标的最后，我们希望显示 MV改变与AD和心血管疾病（无脑血管疾病）的复合有关， 疾病）抑制VEGF和BDNF是用PKCε特异性激活剂预防的。了解影响 脑血管功能障碍对AD病理生理学的影响可能导致开发新的治疗方法， 治疗神经和血管病变，以预防或减缓疾病的进展， 改善受影响或有风险的个人的生活质量。我们的发现可能有助于早期诊断 AD使用脑血管生物标志物，可以识别风险个体。重要的是，我们的发现将 对治疗其他神经退行性疾病和病症，如缺血性 中风和创伤性脑损伤，其中脑血管炎症和突触丢失与 认知障碍

Project Summary/Abstract AD and vascular dementia have been traditionally considered separate pathologies; however, recent data suggest that there is an additive or synergistic effect of cerebrovascular damage and AD pathology on cognitive function. The contribution of cerebrovascular change on AD pathogenesis and progression is an understudied area. Studies of human autopsy brains have shown that the severity of cerebrovascular disease is correlated with dementia, most often dementia attributed to AD. However, the underlying mechanism is not clearly understood, and whether cerebrovascular damage is a causal factor in AD pathogenesis or a consequence of AD progression is not known. Understanding the interaction between the pathogenesis of AD and the pathogenesis of cerebrovascular damage may lead to the development of new therapeutics that can target both. Only over the last ten years, however, have we learned that the same signal molecules, e.g., VEGF and BDNF, influence the growth of neuronal and vascular networks. PKCε activates the mRNA- stabilizing protein Hu, which enhances expression of VEGF and BDNF. A decrease in PKCε occurs in neurons and vascular endothelial cells in aged, AD, and in ischemic brains. We hypothesize that AD pathology results from a combination of neurologic and cardiovascular factors. In Aim 1, we will pathogenesis in neurons and microvasculatures in the human AD and aged-matched control hippocampi from subjects with mixed lesions of hypertension, cardiac disease, and/or cerebrovascular disease. This will provide a thorough understanding of pathogenesis in MV structural changes related to neurons. In Aim 2, we will assess the effect of PKCε activation on early spatial memory defect in transgenic mouse models of AD with and without cerebrovascular disease. Based on our previous results, we expect to show that cerebrovascular disease and MV changes accelerate neuron loss and AD pathogenesis that is protected with the PKCε-enhanced VEGF & BDNF expression. In Aim 3, we will determine the effect of PKCε activation on early spatial memory defect in transgenic mouse models of AD with hypertensive heart disease. At the end of this aim, we expect to show that MV change associated with the complex of AD and cardiovascular disease (without cerebrovascular disease) suppresses VEGF & BDNF is prevented with PKCε-specific activators. Understanding the impact of cerebrovascular dysfunction on AD pathophysiology may lead to the development of new therapeutics that addresses both neuronal and vascular pathologies to prevent or slow the progression of the disease to improve the quality of life of affected or at-risk individuals. Our findings may allow for the earlier diagnosis of AD using cerebrovascular biomarkers that can identify at-risk individuals. Importantly, our findings will have broader implications for the treatment of other neurodegenerative diseases and conditions, such as ischemic stroke and traumatic brain injury, in which cerebrovascular inflammation and synaptic loss correlate with cognitive impairment.