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

经典补体途径在神经胶质表型和多种病理学中在阿尔茨海默病和脑血管疾病中的作用

• 批准号: 10670360
• 负责人: Thor Stein
• 金额: $ 38.03万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670360
• 关键词: Acceleration; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Apolipoprotein E; Arterioloscleroses; Astrocytes; Astrocytosis; Attenuated; Autopsy; Biological Markers; Blood; Blood Glucose; Blood Pressure; Body mass index; Brain; Brain imaging; Brain region; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Classical Complement Pathway; Clinical; Cognitive; Cohort Studies; Collaborations; Communities; Complement; Complement 1q; Complement 4b; Complement component C4a; Data; Development; Elderly; Framingham Heart Study; Functional disorder; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Genotype; Gliosis; Impaired cognition; Inflammatory; Light; Lipids; Magnetic Resonance Imaging; Measures; Monitor; Neurobehavioral Manifestations; Neuropsychology; Participant; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Persons; Phenotype; Population Study; Protein Isoforms; Proteins; RNA Sequence Analysis; Research Project Grants; Resources; Risk; Role; Sampling; Schizophrenia; Single Nucleotide Polymorphism; Subgroup; Symptoms; Synapses; Techniques; Transcript; Variant; age related; aging population; brain tissue; cigarette smoking; cognitive function; cognitive testing; cohort; complement pathway; cytokine; differential expression; frontal lobe; genetic testing; genetic variant; imaging biomarker; insight; mind control; neuroinflammation; neuropathology; new therapeutic target; novel; tau Proteins; tau-1; transcriptome; transcriptome sequencing; vascular risk factor

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.

阿尔茨海默病（AD）的病理基础在老年人群中很常见， 在临床症状出现前十多年此外，衰老增加了多种病理的可能性， 都可能导致认知障碍最近的研究表明，载脂蛋白E（APOE）和 经典补体途径基因参与突触丢失和tau病理学。本项目的目标 目的是研究APOE和补体途径基因在决定神经胶质细胞、神经炎症和 神经病理学改变，最终导致认知和成像生物标志物轨迹改变。我们 在3个具体目标中提出跨学科方法。对于目标1，我们将确定遗传和 补体途径基因的转录风险谱及其与APOE基因型的相互作用 AD中的突触丢失、神经炎症、脑血管疾病和tau病理学 队列以及有脑捐赠的死亡FHS参与者（目前尸检病例数为241; 血液和脑组织，n=208）。对于目标2，我们将确定胶质细胞和神经炎性表型 与AD和脑血管疾病相关的星形胶质细胞增多症、小胶质细胞增生症和脑血管疾病导致独特的模式 导致AD和AD相关疾病的神经炎症，使用新定义的表型， 与神经病理学核心合作开发的传统病理学措施。目标3： 通过确定所鉴定的遗传变异和替代基因的关联来验证临床意义， 目的1和2的转录物和新细胞表型，以及成像生物标志物的纵向变化 和认知功能（n= 3，189）以及定量血管危险因素（例如，血糖、血脂 分数、血压、BMI、吸烟）。我们预计，该项目的结果将提供 开发新的遗传筛选标记和生物标志物的机会，以及对潜在的新的 AD的治疗靶点。