A Molecular Signaling Pathway Underlying Differential Predisposition of ApoE4 Genotype to Alzheimer's Disease

ApoE4 基因型对阿尔茨海默病的差异易感性背后的分子信号通路

基本信息

批准号：
9977878
负责人：
Yu-Wen Alvin Huang
金额：
$ 24.07万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977878
关键词：
Abeta synthesis Address Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Behavior Animals Apolipoprotein E Behavioral Binding Sites Biological Assay Brain CRISPR interference Chronic Data Development Dominant-Negative Mutation Elements Event Future Gene Proteins Genetic Genetic Transcription Genotype Healthcare Hippocampus (Brain)Homo sapiens Human Impaired cognition Inherited Injections Knock-out Knowledge Learning Leucine Zippers Light MAP Kinase Gene MAPK Signaling Pathway Pathway Measures Mediating Memory Mission Molecular Mus Neuroglia Neurons Output Pathogenesis Pathway interactions Peptide Hydrolases Pharmacology Phosphotransferases Predisposition Prevention Primates Promoter Regions Protein Isoforms Public Health Reporter Reporting Research Role Series Signal Pathway Signal Transduction Site Subfamily lentivirinae System Technology Testing Therapeutic Training Transcription Factor AP-1 Transcriptional Regulation Translations United States United States National Institutes of Health Virus abeta deposition apolipoprotein E-3 apolipoprotein E-4 base behavior test career disability experimental study genetic epidemiology genetic risk factor genetic variant human embryonic stem cell in vivo induced pluripotent stem cell innovation knock-down mutant novel novel therapeutics overexpression promoter training opportunity transcription factor β-amyloid burden

项目摘要

PROJECT SUMMARY/ABSTRACT Inheritance of Apolipoprotein E (ApoE) gene variant APOE-ϵ4 is the strongest genetic risk factor for Alzheimer’s disease (AD), a rapidly growing burden of health care for the aging United States. There is a fundamental gap in understanding how expression of APOE-ϵ4, which encodes ApoE isoform ApoE4, influences neuronal function and contributes to AD pathogenesis. This gap, until filled, represents our insufficiency in understanding AD and our inability to provide treatment and prevention to AD and risk carriers. A central event in AD pathogenesis is deposition of amyloid-β (Aβ) peptide, generated from a series of protease cleavages of amyloid precursor protein (APP). Using pure human neurons derived from human embryonic stem cells or iPSCs, the applicant has recently identified a signaling pathway by which ApoE4 stimulates APP transcription and consequently induces Aβ production in neurons, more effectively than the other two isoforms ApoE2 and ApoE3. This pathway hinges on double leucine-zipper kinase DLK and downstream MAPK signaling, and is activated by three ApoE isoforms differentially in the potency rank order of ApoE4>ApoE3>ApoE2, paralleling AD risk rank order. Given this striking ApoE isoform-specific effect, the overall objective of this application is to determine whether and how ApoE4-specific activation of DLK/MAPK signaling pathway may account for ApoE4’s deleterious AD-promoting effect. My central hypothesis is that ApoE4 may predispose to AD by stimulating DLK/MAPK and increasing neuronal Aβ production chronically, and that interference with ApoE-enhanced APP transcription via manipulations of DLK/MAPK pathway may delay AD pathogenesis. I plan to test my central hypothesis, thereby accomplishing the overall objective for this project by pursuing these following specific aims: 1) Determine whether DLK/MAPK pathway mediates differential APP/Aβ induction by ApoE isoforms, ApoE4>ApoE3>ApoE2, 2) Identify the transcription control elements of APP gene required for ApoE stimulation, and 3) Determine the functional output of DLK/MAPK pathway in vivo. A combination of genetic and pharmacological manipulations will be used to enhance or inhibit ApoE-activated DLK/MAPK pathway in cultured neurons and in animal brains. The molecular mechanism and behavioral significance of this pathway will be rigorously examined. The overall approach is innovative because it departs from the status quo by utilizing human neurons and focusing on the underappreciated mechanisms of APP transcription in light of AD pathogenesis. The proposed research is significant, because it is expected to define a new role of ApoE in the brain, and also to explore new therapeutic horizons by targeting DLK-MAPK pathway as an alternative strategy. Findings will advance greatly our knowledge of AD pathogenesis, and have strong potential for future translation into urgently needed treatment and prevention.

项目概要/摘要载脂蛋白 E (ApoE) 基因变异 APOE-ϵ4 的遗传是最强的遗传风险因素阿尔茨海默病 (AD) 是老龄化美国的一个快速增长的医疗负担。理解编码 ApoE 同工型 ApoE4 的 APOE-ϵ4 的表达方式存在根本差距，影响神经功能并促进 AD 发病机制。这个缺口在被填补之前代表了我们的神经功能。对 AD 了解不足，无法为 AD 和风险携带者提供治疗和预防。 AD 发病机制的一个核心事件是淀粉样蛋白-β (Aβ) 肽的沉积，该肽由一系列物质产生使用源自人类的纯人类神经元对淀粉样前体蛋白 (APP) 进行蛋白酶切割。胚胎干细胞或 iPSC，申请人最近发现了 ApoE4 的信号通路刺激 APP 转录，从而诱导神经元中 Aβ 的产生，比其他两种亚型 ApoE2 和 ApoE3 该途径取决于双亮氨酸拉链激酶 DLK 和下游 MAPK 信号传导，并由三种 ApoE 同工型以不同的效力等级顺序激活 ApoE4>ApoE3>ApoE2，与 AD 风险排名顺序平行，考虑到这种显着的 ApoE 同工型特异性效应，本申请的总体目标是确定 DLK/MAPK 是否以及如何特异性激活 ApoE4 信号通路可能解释了 ApoE4 的有害 AD 促进作用。 ApoE4 可能通过刺激 DLK/MAPK 并长期增加神经元 Aβ 的产生而诱发 AD，通过操纵 DLK/MAPK 通路干扰 ApoE 增强的 APP 转录可能我计划检验我的中心假设，从而实现总体目标该项目通过追求以下具体目标：1) 确定 DLK/MAPK 通路是否介导 ApoE 同工型差异 APP/Aβ 诱导，ApoE4>ApoE3>ApoE2，2) 识别转录控制 ApoE 刺激所需的 APP 基因元件，以及 3) 确定 DLK/MAPK 的功能输出遗传和药理学操作的组合将被用来增强或抑制。培养神经元和动物大脑中 ApoE 激活的 DLK/MAPK 通路的分子机制和。该途径的行为意义将受到严格审查，总体方法是创新的。因为它背离了现状，利用人类神经元并关注未被充分认识的事物鉴于 AD 发病机制的 APP 转录机制，这项研究意义重大，因为它预计将定义 ApoE 在大脑中的新作用，并通过靶向探索新的治疗视野 DLK-MAPK 通路作为替代策略的研究结果将极大地增进我们对 AD 的了解。发病机制，并且在未来转化为迫切需要的治疗和预防方面具有强大的潜力。