Impact of APOE on endothelial cell proteomes in Alzheimer's disease

APOE 对阿尔茨海默病内皮细胞蛋白质组的影响

• 批准号: 10606847
• 负责人: Aleksandra Maria Wojtas
• 金额: $ 7.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606847
• 关键词: APP-PS1; Abeta clearance; Acceleration; Affect; Age; Age Months; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Apolipoprotein E; Autopsy; Biological Markers; Biotin; Biotinylation; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Blood flow; Brain; Brain region; Cells; Cerebral Amyloid Angiopathy; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Collection; Coupled; Cre lox recombination system; Data; Dementia; Deposition; Diagnosis; Disease; Disease Progression; Endothelial Cells; Endothelium; Exhibits; Functional disorder; Genes; Genetic Predisposition to Disease; Genome; Genotype; Goals; Health; Histologic; Human; Immunohistochemistry; Impaired cognition; Impairment; Individual; Label; Ligase; Link; Mass Spectrum Analysis; Mediating; Memory; Molecular; Mus; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Pathway interactions; Play; Proteins; Proteome; Proteomics; Research; Resolution; Risk Factors; Role; Sampling; Structure; Techniques; Technology; Testing; Tissues; Variant; Vascular Diseases; Western Blotting; Work; abeta accumulation; abeta deposition; amyloid pathology; apolipoprotein E-3; asymptomatic Alzheimer' s disease; blood-brain barrier permeabilization; brain endothelial cell; brain parenchyma; brain tissue; cell type; cerebrovascular; cerebrovascular pathology; density; disease phenotype; genome wide association study; high risk; in vivo; innovation; insight; mouse model; new therapeutic target; non-demented; normal aging; novel; protein aggregation; religious order study; risk variant; sex; single-cell RNA sequencing; tau aggregation; therapeutic biomarker; therapeutic target; transcriptomics

ABSTRACT (PROJECT SUMMARY) Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that results in deposition of amyloid-b (Ab) peptide in brain parenchyma and cerebral blood vessels as cerebral amyloid angiopathy (CAA). Genome- wide association studies (GWAS) have identified numerous genes altering AD risk with the e4 allele of apolipoprotein E (APOE4) showing the strongest association with AD and CAA. APOE4 modulates amyloid accumulation in cerebrovasculature and impacts the efficiency of Ab clearance from the brain. In addition, APOE4 carriers exhibit accelerated breakdown of the blood-brain barrier (BBB) and higher risk for cerebrovascular dysfunction during normal aging. However, the underlying mechanisms of this genetic susceptibility on cerebrovascular function and pathology are still poorly understood. Recent work from our group revealed APOE-driven protein perturbations associated with endothelial cells in the postmortem brain tissue from AD individuals. Yet, these observations come from bulk brain tissue limiting the ability to dissect cell-type specific proteomic changes. Thus, the major goal of this proposal is to molecularly define the endothelial cells in the context of APOE-associated amyloidosis. I hypothesize that APOE4 genotype directly impacts endothelial proteome leading to the BBB dysfunction and breakdown. In Aim 1, I will perform an unbiased proteomic analysis of isolated cerebral blood vessels from cortical tissues of AD, AD with severe CAA, asymptomatic AD (AsymAD, individuals exhibiting amyloid and tau accumulation in the brain with no cognitive decline), and non-demented control individuals. I will further apply integrative analysis to the brain vascular proteomes and previously generated proteomic data of cerebrospinal fluid (CSF) to identify AD CSF biomarkers that mirror pathological changes of the cerebrovasculature. In Aim 2, I will explore in vivo effect of APOE and amyloid on endothelial cell proteome by taking advantage of highly innovative, recently developed by our group approach that allows for Cell-type specific In-vivo Biotinylation of Proteins followed by mass-spectrometry (CIBOP-MS). Dissecting proteomes of endothelial cells in a disease setting will be a conceptual advancement and a crucial step towards understanding the mechanisms underlying AD-related BBB breakdown, diminished blood flow, and pathological accumulation of amyloid in the cerebrovasculature.

摘要（项目概要） 阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，会导致淀粉样蛋白 B 沉积 (Ab) 脑实质和脑血管中的肽作为脑淀粉样血管病 (CAA)。 广泛关联研究 (GWAS) 已发现许多改变 AD 风险的基因，其 e4 等位基因为 载脂蛋白 E (APOE4) 与 AD 和 CAA 调节淀粉样蛋白的相关性最强。 脑血管系统中的积累并影响抗体从大脑中清除的效率。 APOE4 携带者表现出血脑屏障 (BBB) 的加速破坏和更高的风险 正常衰老过程中的脑血管功能障碍然而，这种遗传的潜在机制。 我们小组最近的工作对脑血管功能和病理学的易感性仍然知之甚少。 揭示了与死后脑组织中的内皮细胞相关的 APOE 驱动的蛋白质扰动 然而，这些观察结果来自大量脑组织，限制了解剖特定细胞类型的能力。 因此，该提案的主要目标是从分子水平上定义内皮细胞。 我认为 APOE4 基因型直接影响内皮细胞。 导致 BBB 功能障碍和崩溃的蛋白质组 在目标 1 中，我将进行公正的蛋白质组分析。 从 AD、伴有严重 CAA 的 AD、无症状 AD（AsymAD、 大脑中出现淀粉样蛋白和 tau 蛋白积累但没有认知能力下降的个体）以及非痴呆患者 我将进一步将综合分析应用于脑血管蛋白质组和之前的研究。 生成脑脊液 (CSF) 的蛋白质组数据，以识别反映病理学的 AD CSF 生物标志物 在目标 2 中，我将探讨 APOE 和淀粉样蛋白对内皮细胞的体内影响。 蛋白质组通过利用我们小组最近开发的高度创新的方法，可以 蛋白质的细胞类型特异性体内生物素化，然后进行质谱分析 (CIBOP-MS)。 疾病环境中内皮细胞的蛋白质组将是一个概念上的进步，也是朝着这一目标迈出的关键一步。 了解 AD 相关 BBB 破坏、血流减少和病理性的潜在机制 淀粉样蛋白在脑血管中的积累。