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）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氏病（AD）发病机理通过多个途径。 APOE不仅与淀粉样蛋白β（Aβ）病理相关，而且还与脑血管相关功能包括血脑屏障完整性和脑血流。鉴于脑血管灾难较早的认知能力下降很大，而apoE绝对在血管中表达壁细胞（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的内容是定义血管壁细胞中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途径。 AIM 1，我们将利用新颖的鼠标模型，其中人APOE2，APOE3或APOE4基因在其上表示通过血管细胞特异性SM22α启动子驱动的CRE切除Loxp Flank Plank的停车盒表达以确定APOE同工型血管壁细胞特异性表达对衰老期间的脑血管功能和脑认知。在AIM 2中，我们将定义APOE同工型的影响使用新颖的脑血管功能障碍和认知能力下降的血管壁细胞缺失 apoe敲入小鼠，其中鼠apoe被Floxed ApoE2，ApoE3或ApoE4基因代替。经过与SM22α-CRE小鼠交叉，我们将在血管壁细胞中特别删除单个APOE同工型。目标 3，我们将研究条件小鼠模型中APOE同工型的血管特异性表达或缺失通过育种血管壁细胞特异性APOE同工型表达或敲除通过繁殖与广告相关的表型具有淀粉样蛋白APP敲除小鼠（AppNL-F/NL-F）的小鼠。使用那些独特的鼠标模型，我们将全面研究血管细胞中的APOE同工型如何影响脑血管功能，神经胶质在不同年龄段的表型，神经炎症，神经退行性，脑认知和淀粉样病理学。在特别是，将通过生物化学和结构分析鼠标模型中的APOE特性建模核心（核心B）。小鼠的APOE量，氧化和/或糖化生物标志物将通过生物标志物核心（核心D）进行测量。而小鼠的神经病理学将是在神经病理学核心（Core C）中进行了研究，这是一种多摩学方法，包括保护性植物学，代谢组学，脂质组学和单细胞RNA测序将通过多摩学核心（核心F）和生物信息学，生物统计学和数据管理核心（核心G）介绍了这些分子表型鼠标模型。共同的创新研究应该填补我们对APOE如何理解的关键空白脑血管管中的同工型会影响细胞功能和脑稳态，并在衰老期间进行AD 通过项目2和项目3，与核心B-G的协同相互作用以及比较小鼠模型研究。