ApoE pathway in cerebrovascular Aβ clearance in Alzheimer's disease

ApoE 通路在阿尔茨海默病脑血管 Aβ 清除中的作用

基本信息

批准号：
9922843
负责人：
GUOJUN BU
金额：
$ 60.67万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922843
关键词：
3-Dimensional Abeta clearance Abeta synthesis Address Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Apolipoprotein E Astrocytes Automobile Driving Biochemical Biological Assay Biological Models Blood - brain barrier anatomy Blood Vessels Brain Breeding Cells Cerebral Amyloid Angiopathy Cerebrovascular Circulation Cerebrovascular system Dementia Deposition Drainage procedure Effectiveness Elderly Endothelial Cells Enzymes Equilibrium Exhibits Funding Genes Genetic Risk Goals Heparan Sulfate Proteoglycan Heparitin Sulfate Human Impairment In Vitro Knockout Mice LDL-Receptor Related Protein 1 Laboratories Late Onset Alzheimer Disease Ligands Low Density Lipoprotein Receptor LoxP-flanked allele MYH11 gene Mediating Metabolism Methods Microdialysis Modeling Molecular Mus Neurons Pathologic Pathology Pathway interactions Patients Pericytes Play Population Prevention Production Protein Isoforms Proteins Role Senile Plaques Signal Pathway Smooth Muscle Myocytes Societies Structure Surface System Tamoxifen Technology Vertebral column abeta accumulation amyloid formation amyloid pathology amyloid precursor protein processing apolipoprotein E-3 apolipoprotein E-4 base beta amyloid pathology brain cell brain parenchyma cell type cerebrovascular cerebrovascular amyloid extracellular genetic risk factor improved in vivo induced pluripotent stem cell knock-down mouse Cre recombinase mouse model promoter receptor receptor binding transcriptome

项目摘要

PROJECT SUMMARY The major goal of this proposal is to define critical cerebrovasculature pathways mediating the clearance of amyloid-β (Aβ), the aggregation of which into amyloid plaques represents a pathological hallmark of Alzheimer's disease (AD). In so doing, we will evaluate the specific role of LDL receptor-related protein 1 (LRP1), heparan sulfate proteoglycan (HSPG) and apolipoprotein E (apoE) isoforms in cerebrovascular clearance of Aβ and formation of cerebral amyloid angiopathy (CAA). The aggregation of Aβ in the brain is a direct result of its increased brain concentration due to an imbalance of its production and clearance. Although brain Aβ clearance is mediated by multiple pathways including intracellular degradation and extracellular degradation, much remains unknown about how the cerebrovasculature system clears Aβ through local cellular, blood-brain barrier (BBB), and perivascular drainage pathways. Given impaired clearance of Aβ drives late-onset AD (LOAD), we aim to improve understanding of the pathways regulating Aβ clearance, thereby establishing new targets for AD therapy and prevention that will benefit the vast majority of patients. During the previous funding cycle, we employed several conditional mouse models to demonstrate that deletion of the Aβ receptor LRP1 leads to slower Aβ clearance and exacerbated amyloid pathology, while deletion of another Aβ receptor HSPG in neurons produces the opposite effects. In addition, we and others have shown that apoE, a ligand for LRP1 and HSPG, modulates Aβ metabolism and pathology in an isoform- dependent manner with apoE4, whose gene allele represents the strongest genetic risk for AD, promoting amyloid deposition and the formation of CAA. Thus, the overall goal of this renewal application is to define the molecular mechanism underlying cerebrovascular clearance of Aβ. We hypothesize that the Aβ receptor LRP1 promotes, whereas HSPG inhibits, Aβ clearance along the cerebrovasculature in an apoE isoform-dependent manner impacting the formation of CAA and the distribution of Aβ pathology. In Aim 1, we will define the roles of LRP1 and HSPG in cerebrovascular function, clearance of Aβ, and formation of amyloid plaques and CAA using conditional mouse models inducing vasculature deletion of Aβ receptors at different ages and at different stages of plaque/CAA pathology. In Aim 2, we will analyze how apoE isoforms affect Aβ clearance and pathology in cerebrovasculature using cell type-specific and inducible mouse models. In Aim 3, we will define the molecular mechanisms through which LRP1, HSPG and apoE isoforms modulate Aβ metabolism, BBB integrity and vascular structure using reconstructed model systems from primary mouse cells or induced pluripotent stem cell (iPSC)-derived human cells to improve the likelihood of discoveries translatable to human AD. Finally, we plan to perform unbiased, single cell-type transcriptome analysis to uncover signaling pathways downstream of LRP1/HSPG/apoE. Together, our studies will define the molecular mechanism(s) underlying brain Aβ clearance and establish new targets for mechanism-based therapy.

项目摘要该提议的主要目标是定义介导的关键脑血管形途径淀粉样蛋白β（Aβ），淀粉样蛋白斑块的聚集代表了病理标志阿尔茨海默氏病（AD）。这样，我们将评估LDL受体相关蛋白1的特定作用（LRP1），硫酸乙酰肝素蛋白聚糖（HSPG）和载脂蛋白E（APOE）同工型在脑血管中 Aβ的清除和脑淀粉样血管病（CAA）的形成。大脑中Aβ的聚集是A 尽管由于其生产和清除率不平衡而导致其脑部浓度增加的直接结果。大脑Aβ清除率是由多种途径介导的，包括细胞内降解和细胞外退化，关于脑瘤系统如何通过局部清除Aβ的降解，尚不清楚细胞，血脑屏障（BBB）和血管周围排水途径。鉴于Aβ驱动器的清除受损晚发广告（负载），我们旨在提高对调节Aβ清除率的途径的理解，从而建立新的广告疗法和预防目标，这将使绝大多数患者受益。在上一个资金周期中，我们采用了几种条件鼠标模型来证明 Aβ受体LRP1的删除导致Aβ清除率较慢和恶化的淀粉样蛋白病理学，而淀粉样蛋白的病理神经元中另一个Aβ受体HSPG的缺失会产生相反的作用。此外，我们和其他人已经表明，APOE是LRP1和HSPG的配体，在同工型中调节Aβ代谢和病理与ApoE4的依赖方式，ApoE4的基因等位基因代表AD的强遗传风险，促进淀粉样蛋白沉积和CAA的形成。这是此续订应用的总体目标是定义 Aβ的脑血管清除的分子机制。我们假设Aβ受体 LRP1促进，而HSPG抑制Aβ沿APOE中的Aβ间隙同工型依赖性方式影响CAA的形成和Aβ病理的分布。在 AIM 1，我们将定义LRP1和HSPG在脑血管功能，清除Aβ和形成中的作用使用条件小鼠模型的淀粉样颗粒斑块和CAA诱导Aβ受体的脉管缺失不同的年龄和在牙菌斑/CAA病理的不同阶段。在AIM 2中，我们将分析APOE同工型使用细胞类型特异性和可诱导的小鼠模型影响脑癌的Aβ清除率和病理。在AIM 3中，我们将定义LRP1，HSPG和APOE同工型调节的分子机制 Aβ代谢，BBB完整性和血管结构使用主要小鼠的重建模型系统细胞或诱导多能干细胞（IPSC）衍生的人类细胞，以改善发现的可能性可以翻译成人类广告。最后，我们计划执行公正的单细胞类型转录组分析发现LRP1/HSPG/APOE下游的信号通路。一起，我们的研究将定义分子脑Aβ的基础机制，并为基于机制的治疗建立了新的靶标。