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Impact of vascular apoE in aging and AD

血管apoE对衰老和AD的影响

基本信息

批准号：
10667475
负责人：
Takahisa Kanekiyo
金额：
$ 54.78万
依托单位：
MAYO CLINIC JACKSONVILLE
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：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667475
关键词：
Acceleration Affect Age Age Months Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein ApoE knockout mouse Apolipoprotein E Astrocytes Atherosclerosis Biochemistry Bioinformatics Biological Markers Biology Biometry Blood - brain barrier anatomy Blood Vessels Brain Brain imaging Breeding Cell model Cell physiology Cells Cerebral Amyloid Angiopathy Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cognition Collaborations Coupling DNA cassette Development Elderly Ensure Excision Genes Genotype Goals Homeostasis Human Immune response Immune system Impaired cognition Individual Knock-in Mouse Knock-out Knockout Mice Lipoproteins Liquid substance LoxP-flanked allele Measures Mediating Metabolism Microglia Modeling Molecular Molecular Profiling Mus Nerve Degeneration Neuroglia Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Pericytes Phase Phenotype Plasma Play Property Protein Isoforms Proteomics Resources Risk Factors Role Sampling Severities Smooth Muscle Myocytes Statistical Data Interpretation Structural Models Study models Testing Vascular Cognitive Impairment White Matter Hyperintensity age related amyloid pathology apolipoprotein E-3 beta amyloid pathology brain parenchyma cell type cerebrovascular cognitive function cognitive performance comparative data management glycation hypercholesterolemia induced pluripotent stem cell innovation lipid metabolism lipid transport lipidomics metabolomics molecular phenotype mouse model multiple omics neuroinflammation neuropathology novel oxidation particle promoter single-cell RNA sequencing white matter damage

项目摘要

PROJECT SUMMARY (APOE U19: Project 4) While the major function of apolipoprotein E (apoE) is to mediate the lipid transport, APOE genotype (APOE2, APOE3 and APOE4) significantly influences cognitive function and Alzheimer’s disease (AD) pathogenesis through multiple pathways. APOE is associated with not only amyloid-β (Aβ) pathology but also cerebrovascular function including blood-brain barrier integrity and cerebral blood flow. Given that cerebrovascular disturbance substantially contributes to cognitive decline in the elderly and that apoE is abundantly expressed in vascular mural cells (smooth muscle cells and pericytes) as well as astrocytes and microglia in the brain, the overall goal of Project 4 is to define how APOE genotype in vascular mural cells impacts the molecular mechanisms and pathways in the development of cerebrovascular dysregulations and cognitive decline during aging and AD. In Aim 1, we will utilize novel mouse models, in which human APOE2, APOE3, or APOE4 gene is expressed upon an excision of a loxp-flanked STOP cassette by vascular mural cell specific sm22α promoter driven Cre expression to determine the effects of vascular mural cell-specific expression of apoE isoforms on cerebrovascular function and brain cognition during aging. In Aim 2, we will define the impact of apoE isoform deletion in vascular mural cells on age-related cerebrovascular dysfunction and cognitive decline using novel APOE knock-in mice, in which murine Apoe is replaced with floxed APOE2, APOE3, or APOE4 gene. By crossing with sm22α-Cre mice, we will specifically delete individual apoE isoforms in vascular mural cells. In Aim 3, we will examine how vascular-specific expression or deletion of apoE isoforms in conditional mouse models affects AD-related phenotypes by breeding the vascular mural cell-specific apoE isoform expressing or knockout mice with amyloid model APP knockin mice (AppNL-F/NL-F). Using those unique mouse models, we will comprehensively investigate how apoE isoforms in vascular mural cells impact cerebrovascular function, glial phenotypes, neuroinflammation, neurodegeneration, brain cognition and amyloid pathology at different ages. In particular, the apoE properties in the mouse models will be analyzed by the Biochemistry and Structural Modeling Core (Core B). ApoE amounts, oxidation and/or glycation in the mice as well as other AD-rerated fluid biomarkers will be measured through the Biomarker Core (Core D). While neuropathology in the mice will be investigated in Neuropathology Core (Core C), a multi-Omics approach including proteomics, metabolomics, lipidomics and single cell RNA sequencing will be carried out through the Multi-Omics Core (Core F) and Bioinformatics, Biostatistics, and Data Management Core (Core G) to profile molecular phenotypes in these mouse models. Together, our innovative study should fill a critical void in our understanding of how apoE isoforms in cerebrovasculature impact cellular functions and brain homeostasis during aging and AD through synergistic interaction with Core B-G and comparative mouse model studies by Project 2 and Project 3.

项目摘要（APOE U19：项目 4）虽然载脂蛋白 E (apoE) 的主要功能是介导脂质转运，但 APOE 基因型 (APOE2、 APOE3 和 APOE4) 显着影响认知功能和阿尔茨海默病 (AD) 发病机制通过多种途径。 APOE 不仅与淀粉样蛋白-β (Aβ) 病理学相关，还与脑血管疾病相关功能包括血脑屏障完整性和脑血流量。鉴于脑血管障碍 apoE 在很大程度上导致老年人的认知能力下降，并且 apoE 在血管中大量表达壁细胞（平滑肌细胞和周细胞）以及大脑中的星形胶质细胞和小胶质细胞，总体目标项目 4 的目的是定义血管壁细胞中的 APOE 基因型如何影响分子机制和衰老和 AD 期间脑血管失调和认知能力下降的发展途径。在目标 1，我们将利用新的小鼠模型，其中表达人类 APOE2、APOE3 或 APOE4 基因通过血管壁细胞特异性 sm22α 启动子驱动的 Cre 切除 loxp 侧翼的 STOP 盒表达以确定 apoE 亚型的血管壁细胞特异性表达对衰老过程中的脑血管功能和大脑认知。在目标 2 中，我们将定义 apoE 同工型的影响血管壁细胞缺失对年龄相关脑血管功能障碍和认知能力下降的影响 APOE 敲入小鼠，其中小鼠 Apoe 被 floxed APOE2、APOE3 或 APOE4 基因取代。经过与 sm22α-Cre 小鼠杂交，我们将特异性删除血管壁细胞中的单个 apoE 同工型。瞄准 3、我们将研究条件小鼠模型中apoE亚型的血管特异性表达或缺失如何通过培育血管壁细胞特异性 apoE 亚型表达或敲除来影响 AD 相关表型淀粉样蛋白模型 APP 敲入小鼠 (AppNL-F/NL-F)。使用这些独特的鼠标模型，我们将全面研究血管壁细胞apoE亚型如何影响脑血管功能、神经胶质细胞不同年龄的表型、神经炎症、神经变性、大脑认知和淀粉样蛋白病理。在特别是，小鼠模型中的 apoE 特性将通过生物化学和结构分析进行分析建模核心（核心 B）。小鼠中的 ApoE 含量、氧化和/或糖化以及其他 AD 相关液体生物标记物将通过生物标记物核心（Core D）进行测量。虽然小鼠的神经病理学将神经病理学核心（核心 C）进行了研究，这是一种多组学方法，包括蛋白质组学、代谢组学、脂质组学和单细胞 RNA 测序将通过多组学核心（Core F）和生物信息学、生物统计学和数据管理核心 (Core G)，用于分析这些领域的分子表型鼠标模型。总之，我们的创新研究应该填补我们对 apoE 如何理解的一个关键空白。脑血管系统中的亚型通过以下方式影响衰老和 AD 过程中的细胞功能和大脑稳态与 Core B-G 的协同相互作用以及项目 2 和项目 3 的比较小鼠模型研究。