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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 -总结