Role of classical complement pathway underling glial phenotypes and multiple pathologies in Alzheimer's disease and cerebrovascular disease

阿尔茨海默病(AD)的病理基础在老年人群中很常见，而且更容易发生 比临床症状早十年。此外，衰老增加了患上多种病理疾病的可能性 可能都会导致认知障碍。最近的研究表明，载脂蛋白E(APOE)和 经典的补体途径基因参与突触丢失和tau病理。这个项目的目标是 目的是研究载脂蛋白E和补体途径基因在决定神经胶质细胞、神经炎性和 最终导致认知和成像生物标记物轨迹改变的神经病理改变。我们 在3个具体目标中提出跨学科的方法。对于目标1，我们将确定遗传和 补体途径基因转录风险谱及其与载脂蛋白E基因的相互作用 使用整个FHS对AD患者的突触丢失、神经炎症、脑血管疾病和tau病理进行研究 脑部捐献的队列和已故FHS参与者(目前尸检病例数为241例； 取血和脑组织，n=208)。对于目标2，我们将确定神经胶质和神经炎性表型 与AD和脑血管疾病相关的导致星形细胞增多症、小胶质细胞增多症和 神经炎症导致AD和AD相关疾病使用新定义的表型和 传统的病理测量是与神经病理学核心合作开发的。对于目标3，我们将 通过确定已识别的基因变异和替代基因之间的关联来验证临床意义 AIMS 1和AIMS 2的转录本和新的细胞表型及其成像生物标志物的纵向变化 和认知功能(n=3,189)以及定量的血管危险因素(如血糖、血脂 分数、血压、BMI、吸烟)。我们预计这个项目的结果将提供 开发新的遗传筛选标记和生物标记的机会以及对潜在新事物的洞察 AD的治疗靶点。

The pathologies underlying Alzheimer disease (AD) are common in the aged population and can occur more than a decade prior to clinical symptoms. In addition, aging increases the likelihood of multiple pathologies which may all contribute to cognitive impairment. Recent studies demonstrate that apolipoprotein E (APOE) and classical complement pathway genes are involved in synaptic loss and tau pathology. The objective of this project is to investigate role of APOE and complement pathway genes in determining glial, neuroinflammatory, and neuropathological alterations that ultimately lead to altered cognitive and imaging biomarker trajectories. We propose a cross-disciplinary approach in 3 specific aims. For Aim 1, we will determine how genetic and transcriptional risk profiles of complement pathway genes and their interaction with APOE genotype contribute to synaptic loss, neuroinflammation, cerebrovascular disease, and tau pathology in AD using the entire FHS cohort as well as within deceased FHS participants with brain donation (current number of autopsy cases is 241; with blood and brain tissue, n=208). For Aim 2, we will determine how glial and neuroinflammatory phenotypes associated with AD and cerebrovascular disease result in distinctive patterns of astrocytosis, microgliosis, and neuroinflammation that lead to AD and AD-related disorders using newly defined phenotypes together with traditional pathological measures developed in collaboration with the Neuropathology Core. For Aim 3, we will validate clinical implications by determining associations of the identified genetic variants and alternative transcripts and novel cellular phenotypes from Aims 1 and 2 with longitudinal changes of imaging biomarkers and cognitive function (n=3,189) as well as with quantitative vascular risk factors (e.g., blood glucose, lipid fractions, blood pressure, BMI, cigarette smoking). We anticipate that results from this project will provide opportunities for developing new genetic screening markers and biomarkers and insights about potential novel therapeutic targets for AD.