Cell autonomous and non-cell autonomous roles of the GWAS risk factor BIN1 in Alzheimer's disease neuropathology

GWAS 危险因子 BIN1 在阿尔茨海默病神经病理学中的细胞自主和非细胞自主作用

基本信息

批准号：
9198396
负责人：
GOPAL THINAKARAN
金额：
$ 206.06万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198396
关键词：
Adaptor Signaling Protein Age Alleles Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloidosis Apoptosis Attenuated Behavior Behavioral Biological Brain Cell Cycle Progression Cells Centronuclear myopathy Complex Confocal Microscopy Cytoskeletal Modeling DNA Repair DNA Sequence Alteration Dendrites Deposition Disease Down-Regulation Drug or chemical Tissue Distribution Employee Strikes Endocytosis Etiology Exons Family Foundations Fractionation Future Genes Genetic study Goals Hippocampal Mossy Fibers Human Immunoelectron Microscopy In Vitro Individual Intervention Investigation Knock-out Knockout Mice Late Onset Alzheimer Disease Learning Link Membrane Modeling Mus Muscular Atrophy Neonatal Nerve Degeneration Neurodegenerative Disorders Neurons Oligodendroglia Pathology Pathway interactions Play Process Protein Family Protein Isoforms Proteins Reporting Risk Factors Rodent Role Senile Plaques Staining method Stains Susceptibility Gene Tauopathies Testing Tissues Transcript Transgenic Mice Transgenic Organisms Translating Variant amphiphysin attenuation base cell type critical period fly genome wide association study gray matter in vivo innovation insight interest member mouse model myelination neuronal cell body neuropathology novel novel strategies prevent risk variant tau Proteins white matter

项目摘要

This proposal focuses on BIN1, one of the recently identified common risk genes within the major susceptibility loci for late-onset Alzheimer's disease (LOAD) (second only to APOE). BIN1 (Bridging INtegrator-1) is a member of a family of adaptor proteins that regulate membrane dynamics in the context of endocytosis and membrane remodeling. Alternate splicing of the 20 exons in BIN1 gene generates ubiquitous and tissue- specific isoforms, which differ in their tissue distribution, subcellular localization, and function. These functions include cell cycle progression, apoptosis, cytoskeletal organization, and DNA repair. An increase of BIN1 expression and alternate splicing of BIN1 have been reported in the brains of individuals with LOAD but how these observations translate to increased risk for AD is entirely not clear. In preliminary studies, we have characterized prominent BIN1 expression in mature oligodendrocytes in the gray and white matter in rodent and the human brain. By generating oligodendrocyte-specific Bin1 conditional knock out (cKO) mice, we confirmed that BIN1 is mainly expressed in mature oligodendrocytes. Interestingly, we observe aberrant BIN1 expression near human senile plaques and BIN1 accrual in amyloid deposits of AD transgenic mouse models. Based on these novel findings, we hypothesize that BIN1 functions in mature oligodendrocytes, and that alteration in BIN1 expression and/or function in oligodendrocytes plays a role in AD-related pathogenic processes and neurodegeneration in a non-cell autonomous manner. We propose the following specific aims to test novel hypothesis related to the role of BIN1 in AD. The Specific Aims of this proposal are: Aim 1: To test the hypothesis that BIN1 cellular expression and localization are altered in AD brain. We will investigate the BIN1 expression and alternate splicing in normal and diseased human brain. We will determine the subcellular localization of BIN1 by fractionation and confocal microscopy, and clarify the ultrastructural BIN1 localization using immunoelectron microscopy. Aim 2: To test the hypothesis that downregulation of BIN1 expression will attenuate amyloid and tau pathology in transgenic mice. We will ascertain whether cell-type specific loss of BIN1 expression in neurons or mature oligodendrocytes will attenuate AD-related neuropathology and behavior deficits in transgenic AD mouse models. Aim 3: To test the hypothesis that BIN1 plays a role in oligodendrocyte differentiation, survival, and maturation, as well as myelination in vivo. We will utilize Bin1 cKO mouse models and cultured oligodendrocytes to test this hypothesis. This proposal is timely, unique, and highly innovative. We believe that our investigation will uncover significant insights on BIN1's function in the brain, characterize novel Bin1 cKO mouse models of interest to the AD field, establish whether attenuation of BIN1 expression provides a novel strategy for disease intervention, and lay the foundation for characterization of BIN1 functional variants linked to AD, and guide future functional characterization of biological pathways and pathogenic mechanisms regulated by this major LOAD risk gene.

该提案的重点是BIN1，BIN1是最近发病的阿尔茨海默氏病（负载）（仅次于APOE）的主要易感基因座中最近确定的常见风险基因之一。 BIN1（BRIDGING INTIGHOTOR-1）是在内吞作用和膜重塑的背景下调节膜动力学家族的成员。 BIN1基因中20个外显子的替代剪接会产生无处不在的组织 - 特异性同工型，它们的组织分布，亚细胞定位和功能不同。这些功能包括细胞周期进展，凋亡，细胞骨架组织和DNA修复。在有负载的个体的大脑中，已经报道了BIN1表达和BIN1的替代剪接的增加，但是这些观察结果如何转化为AD的风险增加尚不清楚。在初步研究中，我们表征了啮齿动物和人脑中灰质和白质成熟的少突胶质细胞中的显着BIN1表达。通过产生少突胶质细胞特异性BIN1条件敲除（CKO）小鼠，我们确认BIN1主要在成熟的少突胶质细胞中表达。有趣的是，我们在AD转基因小鼠模型的淀粉样蛋白沉积中观察到人类老年斑块附近的异常BIN1表达。基于这些新的发现，我们假设BIN1在成熟的少突胶质细胞中起作用，并且BIN1表达和/或功能的变化在少突胶质细胞中起作用在与AD相关的致病过程中起作用，而在非电池自治方式中的神经变性则起着作用。我们提出以下特定目的，以检验与BIN1在AD中的作用相关的新假设。该提案的具体目的是：目标1：测试BIN1细胞表达和定位在AD大脑中发生改变的假设。我们将在正常和患病的人脑中研究BIN1表达和替代剪接。我们将通过分馏和共聚焦显微镜确定BIN1的亚细胞定位，并使用免疫电子显微镜阐明超微结构BIN1定位。目的2：检验以下假设：BIN1表达的下调会减弱转基因小鼠中的淀粉样蛋白和tau病理。我们将确定在神经元或成熟的少突胶质细胞中BIN1表达的细胞类型特异性损失是否会减弱与转基因AD小鼠模型中与AD相关的神经病理学和行为缺陷。目标3：检验BIN1在少突胶质细胞分化，生存和成熟以及体内髓鞘化中起作用的假设。我们将利用BIN1 CKO小鼠模型和培养的少突胶质细胞来检验该假设。该建议是及时，独特且高度创新的。我们认为，我们的研究将发现对BIN1在大脑中功能的重大见解，将新型BIN1 CKO鼠标感兴趣的新型CKO鼠标模型中的广告领域模型，确定BIN1表达的衰减是否为疾病干预提供了新的策略，并为与AD链接的BIN1功能变体的表征奠定了基础，并指导了通过这种生物学途径和途径的途径进行了依据。