Influence of APOE genotype on cerebrovascular cell pathobiology in AD, and the contribution of microglia inflammation

APOE基因型对AD脑血管细胞病理学的影响以及小胶质细胞炎症的贡献

基本信息

批准号：
10468189
负责人：
Joseph O Ojo
金额：
$ 16.2万
依托单位：
ROSKAMP INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468189
关键词：
Ablation Address Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Apolipoprotein E Automobile Driving Autopsy Blood - brain barrier anatomy Blood Vessels Blood flow Brain Cells Cerebral Amyloid Angiopathy Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular system Cerebrum Clinical Clinical Trials Cognitive Dementia Deposition Disease Disease associated microglia Endothelial Cells Etiology Event Future Generations Genes Genetic Transcription Genotype Goals Health Hemorrhage Human Human Pathology Impairment Inflammation Knock-in Mouse Leptomeninges Lesion Longitudinal Studies Maps Mediating Microglia Modeling Molecular Mus Nerve Degeneration Neurofibrillary Tangles Neuroglia Neurologic Neurologic Dysfunctions Neuronal Dysfunction Neurons Newborn Infant Outcome Pathogenesis Pathogenicity Pathology Patients Perfusion Pericytes Phenotype Play Population Protein Isoforms Proteomics Recurrence Reporting Research Research Design Risk Risk Factors Role Senile Plaques Smooth Muscle Myocytes Symptoms System Techniques Therapeutic Time TimeLine Tissues Toxic effect Transcript Validation Vascular Diseases Vascular Smooth Muscle Work age related neurodegeneration aging brain amyloid pathology apolipoprotein E-4 arteriole base cerebrovascular cerebrovascular health cerebrovascular lesion cognitive function differential expression healthy aging hemodynamics human model mind control mouse model mutant neurovascular novel novel therapeutic intervention novel therapeutics phase III trial pre-clinical prodromal Alzheimer&apos s disease response restoration tau Proteins therapeutic target tissue mapping transcriptomics

项目摘要

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder and the predominant type of dementia, marked by brain deposits of amyloid plaques and neurofibrillary tangles. An often overlooked pathognomonic lesion of AD is cerebrovascular degeneration. Abnormalities in cerebral blood flow are a preclinical feature of AD that manifest many years before symptom onset. Vascular lesions are also routinely observed in AD brains at different stages of the disease. Disruptions to cerebrovascular integrity can impact on neuronal function, however, the main driver of these vascular changes in AD remains elusive. The Apolipoprotein E4 (APOE4) allele is one of the strongest risk factors for AD, and has been shown to significantly impact on cerebrovascular health, precipitating deficits in cerebral perfusion, vascular lesions and damage to the blood brain barrier. Yet, more longitudinal studies are needed to better understand how APOE4 can significantly impact on cerebrovascular cell pathobiology in the sequelae of AD pathogenesis. In the brain, APOE is produced primarily by glial cells, and in AD, disease associated microglia (DAM’s) are known to upregulate APOE expression, which mediates the transcriptional proinflammatory phenotype of these cells. DAM’s have been shown to drive the outcome and pace of APOE-mediated neuronal dysfunction, but very little is currently known about the role they play in contributing to cerebrovascular changes in AD, particularly, how this is influenced by APOE genotype. To address these questions, we plan to use mouse models expressing human forms of APOE and A𝛽 to clarify the role played by APOE4 as a molecular driver of cerebrovascular cell pathobiology, and how this is influenced by DAM’s. We will explore longitudinal cerebrovascular cell pathobiology at timepoints representing pre, peri and post onset of A 𝛽 pathology using histopathological and ultrastructural analyses. We will also confirm the contribution of DAMs on cerebrovascular pathobiology by utilizing microglia ablation techniques to depopulate DAMs and also repopulate newborn microglia in our mouse models. To date, no studies have characterized the molecular transcripts of reactive cerebrovascular cell phenotypes in these combined models. Thus, we will conclude our studies using single cell gene analyses of cerebrovascular cells (endothelial cells, pericytes, smooth muscle cells) to reveal their unique and detailed time-course of responses. We will confirm differentially expressed genes in autopsied cerebrovascular tissue from staged AD cases to validate the translational relevance of our findings and map against mouse AD-related pathogenic timelines. From this proposal, we aim to identify novel (cerebrovascular) cell specific targets in the early stages of disease through which the APOE4 allele confers neurological risk. Our future goal will be to explore the functional effects of these targets, and to provide new therapeutic opportunities to promote cerebrovascular health and restoration of cognitive function in AD.

阿尔茨海默氏病（AD）是一种与年龄有关的神经退行性疾病，是主要类型痴呆症，以淀粉样蛋白斑块和神经纤维缠结的脑沉积物为特征。经常被忽视 AD病变是脑血管变性。脑血流异常是 AD的临床前特征在症状发作之前多年表现出来。血管病变也常规在疾病的不同阶段观察到在广告大脑中观察到。对脑血管完整性的破坏会影响然而，神经元功能的AD中这些血管变化的主要驱动力仍然难以捉摸。载脂蛋白E4（APOE4）等位基因是AD的强大风险因素之一，已被证明是对脑血管健康的显着影响，在脑灌注，血管病变和损害血脑屏障。但是，需要更多的纵向研究来更好地了解APOE4 在AD发病机理的后遗症中，可以显着影响脑血管细胞病理生物学。在大脑中，APOE主要由神经胶质细胞产生，在AD中，疾病相关的小胶质细胞（DAM）产生已知可以上调APOE表达，它介导了转录促炎的表型这些细胞。大坝已被证明可以推动ApoE介导的神经元功能障碍的结果和空间，但是，目前，他们在促进AD脑血管变化方面所扮演的作用知之甚少，特别是，这如何受APOE基因型的影响。为了解决这些问题，我们计划使用表达人类形式的apoe和a𝛽的鼠标模型阐明APOE4作为脑血管细胞病理学的分子驱动器的作用，以及如何受大坝的影响。我们将在时间点探索纵向脑血管病理生物学代表前，PERI和后发作一个 𝛽使用组织病理学和超微结构分析的病理学。我们还将通过使用小胶质细胞消融来确认大坝对脑血管病理生物学的贡献在我们的小鼠模型中减少大坝并重新填充新生小胶质细胞的技术。迄今为止，没有研究表征了反应性脑血管细胞表型的分子转录本组合模型。这，我们将使用脑血管细胞的单细胞基因分析进行研究（内皮细胞，周细胞，平滑肌细胞），以揭示其独特而详细的反应时间。我们将确认从上演的AD病例到尸检的脑血管组织中不同表达的基因验证我们的发现的翻译相关性和针对与小鼠广告相关的致病时间表的映射。根据该提议，我们旨在在早期的早期阶段确定新颖（脑血管）特定靶标 APOE4等位基因承认神经系统风险的疾病。我们未来的目标是探索这些目标的功能效果，并提供新的治疗机会来促进脑血管 AD中认知功能的健康和恢复。