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.

项目总结 本研究的重点是BIN1，这是最近发现的主要易感基因之一 迟发性阿尔茨海默病(LOAD)的基因座(仅次于APOE)。BIN1(桥接积分器-1)是一个 适配蛋白家族的成员，在内吞作用中调节膜动力学，并 膜重塑。BIN1基因20个外显子的交替剪接产生无处不在的和组织的- 特定的异构体，在组织分布、亚细胞定位和功能上有所不同。这些函数 包括细胞周期进程、细胞凋亡、细胞骨架组织和DNA修复。BIN1的增加 BIN1的表达和交替剪接已被报道在负荷个体的大脑中，但如何 这些观察结果会增加AD的风险是完全不清楚的。在初步研究中，我们有 啮齿动物灰质和白质成熟少突胶质细胞中BIN1的显著表达 还有人类的大脑。通过产生少突胶质细胞特异性BIN1条件性基因敲除(CKO)小鼠，我们 证实BIN1主要在成熟少突胶质细胞中表达。有趣的是，我们观察到异常的BIN1 AD转基因小鼠模型的淀粉样蛋白沉积中近人类老年斑的表达和BIN1的表达。 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 少突胶质细胞BIN1表达和/或功能改变在AD相关发病中的作用 以非细胞自主的方式进行过程和神经退化。我们提出了以下具体建议 目的验证与BIN1在AD中的作用相关的新假说。这项建议的具体目标是：目标1： 验证BIN1细胞在AD脑内表达和定位改变的假说。我们会调查的 BIN1在正常和疾病人脑组织中的表达和交替剪接。我们将确定 BIN1的亚细胞定位及超微结构研究 使用免疫电子显微镜进行定位。目的2：检验BIN1下调的假设 表达将减轻转基因小鼠的淀粉样蛋白和tau蛋白的病理。我们将确定细胞类型 神经元或成熟少突胶质细胞中BIN1表达的特异性缺失将减弱AD相关 转基因AD小鼠模型的神经病理和行为缺陷。目标3：检验假设 在体内，BIN1在少突胶质细胞的分化、存活和成熟以及髓鞘形成中起着重要作用。我们 将利用BIN1 CKO小鼠模型和培养的少突胶质细胞来验证这一假说。这项建议是 及时、独特、高度创新。我们相信，我们的调查将发现关于 BIN1的S的大脑功能，表征了AD领域感兴趣的新型BIN1CKO小鼠模型，建立 BIN1表达减弱是否为疾病干预提供了一种新的策略，并奠定了 为鉴定与AD相关的BIN1功能变体奠定基础，并指导未来的功能 这一主要负荷风险基因调控的生物学途径和致病机制的特征。

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