Project 1: Differential Roles of ApoE Isoforms in Neural Network Dysfunction of Alzheimer's Disease

项目 1：ApoE 同工型在阿尔茨海默病神经网络功能障碍中的不同作用

基本信息

批准号：
10670337
负责人：
YADONG HUANG
金额：
$ 94.27万
依托单位：
J. DAVID GLADSTONE INSTITUTES
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：
2021-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670337
关键词：
Abeta synthesis Affect Age Age of Onset Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid beta-Protein Apolipoprotein E Astrocytes Behavioral Brain region Cell Culture Techniques Cells Clinical Research Cognition Collaborations Dose Enterobacteria phage P1 Cre recombinase Etiology Frontotemporal Dementia Genes Genetic Hippocampus Human Individual Knock-in Knowledge LoxP-flanked allele Microglia Molecular Mus Nature Network-based Neurofibrillary Tangles Neurons Pathogenesis Pathologic Pathology Pathway interactions Population Study Program Research Project Grants Protein Isoforms Role Virulence Factors age related apolipoprotein E-4 cell type genetic risk factor insight mouse model mutant network dysfunction neural network neurofibrillary tangle formation novel prevent single nucleus RNA-sequencing tau Proteins therapeutic target therapy development transcriptomics

项目摘要

PROJECT 1 – SUMMARY The complexity and multifactorial nature of Alzheimer’s disease (AD) pose unique challenges for mechanistic studies and developing therapies. Although the three major pathogenic factors of AD—amyloid-beta peptides, tau, and apolipoprotein E4 (apoE4)—have been extensively studied as independent entities in AD pathogenesis, efforts to target individual AD-related pathways, such as Ab production or clearance, have largely failed in human trials. Emerging evidence strongly suggests that AD is a consequence of age-dependent neural network dysfunction in brain regions that mostly affect cognition, likely through the interactive effects of multiple pathogenic factors. Thus, there is a pressing need to identify novel mechanisms and therapeutic targets, at a neural network level and in the context of interactions between multiple pathogenic factors—the focus of this proposal. APOE4, which encodes one of the three major isoforms of apoE in humans, is the major genetic risk factor for AD and lowers the age of onset in a gene dose-dependent manner. In most clinical studies, APOE4 carriers account for 60–75% of AD cases, highlighting the importance of APOE4 in AD pathogenesis. On the other hand, many clinical and population studies show that APOE2, encoding the rarest apoE isoform, is a strongly protective genetic factor in AD. A pathological hallmark of AD is the formation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated, insoluble tau, containing both 3R and 4R tau isoforms. In cell cultures and mouse models, apoE isoforms have tau-dependent differential effects, and tau has apoE isoform-dependent effects, suggesting interactive roles in AD pathogenesis. However, almost all of these studies of apoE isoforms and tau drew conclusions based either on mouse tau, which is present almost exclusively as 4R tau, or on mutant human tau, which is associated with frontotemporal dementia but not AD. In Project 1, we propose to determine cell- type-specific, differential roles of apoE isoforms in age-dependent neural network dysfunction and behavioral deficits, in the context of wildtype (WT) human tau (both 3R and 4R tau isoforms), in novel mouse models of AD. In Aim 1, we will determine differential roles of apoE isoforms in neural network dysfunction and behavioral deficits, using apoE-isoform-floxed knock-in (APOEfE2/fE2 [fE2], APOEfE3/fE3 [fE3], and APOEfE4/fE4 [fE4]) mice expressing WT human tau (MAPT knock-in or TAUWT) at different ages. In Aim 2, we will determine cell-type- specific, differential roles of apoE isoforms in neural network dysfunction and behavioral deficits, using fE2/TAUWT, fE3/TAUWT, and fE4/TAUWT mice expressing cell-type-specific Cre recombinase (neuron-specific Cresyn1, astrocyte-specific CreGFAP, and microglia-specific CreCx3cr1) in order to delete the APOE allele in a cell- type-specific manner. The studies in this project, together with those of the three other projects of this program project grant, will yield new insights into the multifactorial pathogenesis of AD and may identify neural network- based targets for apoE isoform–dependent and cell type-specific therapies to treat or prevent AD.

项目1 - 摘要阿尔茨海默氏病（AD）的复杂性和多因素性质为机械带来了独特的挑战研究和开发疗法。尽管AD的三个主要致病因素 - 淀粉样蛋白β肽， tau和载脂蛋白E4（APOE4） - 在AD发病机理中被广泛研究为独立实体，努力针对单个与广告相关的途径，例如AB的生产或清除率，在人类中已经失败了试验。新兴证据强烈表明AD是年龄依赖神经网络的结果大脑区域的功能障碍主要影响认知，这可能是通过多重的互动效应致病因素。这是在一个紧迫的需要确定新的机制和治疗靶标神经网络水平以及多种致病因素之间的相互作用的背景提议。 APOE4编码人类APOE的三个主要同工型之一，是主要的遗传风险因素 AD并以基因剂量依赖性方式降低发作年龄。在大多数临床研究中，APOE4载体占AD病例的60-75％，突出了APOE4在AD发病机理中的重要性。另一方面，许多临床和人群研究表明，编码最稀有的APOE同工型的APOE2是一个受到强烈保护的 AD中的遗传因素。 AD的病理标志是形成神经原纤维缠结（NFTS）的形成含有3R和4R tau同工型的高磷酸化，不溶性tau。在细胞培养和小鼠中模型，APOE同工型具有tau依赖性差异效应，而tau具有APOE同工型依赖性效应，暗示在AD发病机理中的互动作用。但是，几乎所有对APOE同工型和TAU的研究德鲁的结论是基于小鼠tau的，该结论几乎仅作为4R tau或突变的人类 tau，与额颞痴呆相关，但无关。在项目1中，我们建议确定细胞 ApoE同工型在年龄依赖性神经网络功能障碍和行为中的类型特异性差异作用在新型的AD小鼠模型中，在Wildtype（WT）人Tau（3R和4R TAU同工型）的背景下，缺陷。在AIM 1中，我们将确定APOE同工型在神经网络功能障碍和行为中的差异作用定义使用apoe-异型 - 粘合敲入（apoefe2/fe2 [fe2]，apoefe3/fe3 [fe3]和apoefe4/fe4 [fe4]）小鼠在不同年龄段表达wt人tau（mapt敲门或tauwt）。在AIM 2中，我们将确定细胞类型 APOE同工型在神经网络功能障碍中的特定，不同的作用，并使用行为定义，使用 Fe2/tauwt，fe3/tauwt和Fe4/tauwt小鼠表达细胞型特异性CRE重组酶（神经元特异性为了删除细胞中的ApoE等位基因特定于类型的方式。该项目的研究以及该计划的其他三个项目的研究项目赠款将产生对AD多因素发病机理的新见解，并可以识别神经网络 - 基于APOE同工型依赖性和细胞类型特异性疗法的靶标，以治疗或预防AD。