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

• 批准号: 10176956
• 负责人: GOPAL THINAKARAN
• 金额: $ 87.59万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176956
• 关键词: Cell; autonomous; non; cell; roles

PROJECT SUMMARY 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.

项目摘要 这项提案的重点是BIN 1，这是最近在主要易感性中发现的共同风险基因之一。 晚发性阿尔茨海默病（LOAD）（仅次于APOE）的基因座。BIN 1（Bridging Integrator-1）是一种 在胞吞作用中调节膜动力学的衔接蛋白家族成员， 膜重塑BIN 1基因中20个外显子的选择性剪接产生了普遍存在的和组织- 特异性同种型，其组织分布、亚细胞定位和功能不同。这些功能 包括细胞周期进程、凋亡、细胞骨架组织和DNA修复。增加BIN 1 BIN 1的表达和选择性剪接已经在LOAD患者的大脑中被报道，但是如何表达和选择性剪接BIN 1呢？ 这些观察结果转化为AD风险的增加完全不清楚。在初步研究中， 在啮齿类动物的灰质和白色物质中，BIN 1在成熟的少突胶质细胞中表达显著 和人类的大脑。通过产生少突胶质细胞特异性Bin 1条件性敲除（cKO）小鼠，我们 证实BIN 1主要在成熟的少突胶质细胞中表达。有趣的是，我们观察到异常的BIN 1 在AD转基因小鼠模型的淀粉样沉积物中，在人老年斑附近的表达和BIN 1的增加。 基于这些新的发现，我们假设BIN 1在成熟的少突胶质细胞中起作用， 在少突胶质细胞中BIN 1表达和/或功能的改变在AD相关的致病性中起作用。 过程和神经退行性变的非细胞自主的方式。我们提出以下具体建议： 目的是测试与BIN 1在AD中的作用相关的新假设。该提案的具体目标是：目标1： 为了验证BIN 1细胞表达和定位在AD脑中改变的假设。我们将调查 正常和病变人脑中BIN 1表达和可变剪接。康贝特人将以 通过分级分离和共聚焦显微镜对BIN 1进行亚细胞定位，并阐明BIN 1的超微结构 使用免疫电子显微镜定位。目的2：为了检验BIN 1下调 表达将减弱转基因小鼠中的淀粉样蛋白和tau病理。我们将确定细胞类型 在神经元或成熟少突胶质细胞中BIN 1表达的特异性缺失将减弱AD相关的 在转基因AD小鼠模型中的神经病理学和行为缺陷。目标3：检验假设， BIN 1在体内少突胶质细胞分化、存活和成熟以及髓鞘形成中起作用。我们 将利用Bin 1 cKO小鼠模型和培养的少突胶质细胞来检验这一假设。这项建议是 及时，独特，高度创新。我们相信，我们的调查将揭示重要的见解， BIN 1在脑中的功能，表征AD领域感兴趣的新型Bin 1 cKO小鼠模型，建立 BIN 1表达的减弱是否为疾病干预提供了一种新的策略， 为表征与AD相关的BIN 1功能变体奠定基础，并指导未来的功能 表征由该主要LOAD风险基因调控的生物学途径和致病机制。

项目成果

Significance of cytosolic cathepsin D in Alzheimer's disease pathology: Protective cellular effects of PLGA nanoparticles against β-amyloid-toxicity.

• DOI: 10.1111/nan.12647
• 发表时间: 2020-12
• 期刊: Neuropathology and applied neurobiology
• 影响因子: 5
• 作者: Wang Y;Wu Q;Anand BG;Karthivashan G;Phukan G;Yang J;Thinakaran G;Westaway D;Kar S
• 通讯作者: Kar S

Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model.

前脑 BIN1 的缺失会减轻 tau 蛋白病模型中的海马病理学和神经炎症。

• DOI: 10.1093/brain/awac318
• 发表时间: 2023
• 期刊: Brain : a journal of neurology
• 作者: Ponnusamy,Moorthi;Wang,Shuai;Yuksel,Melike;Hansen,MitchellT;Blazier,DanielleM;McMillan,JosephD;Zhang,Xiaolin;Dammer,EricB;Collier,Lisa;Thinakaran,Gopal
• 通讯作者: Thinakaran,Gopal