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.

项目概要 该提案重点关注 BIN1，这是最近发现的主要易感性中的常见风险基因之一 晚发性阿尔茨海默病 (LOAD) 位点（仅次于 APOE）。 BIN1（桥接集成器-1）是一个 衔接蛋白家族的成员，可在内吞作用的背景下调节膜动力学 膜重塑。 BIN1 基因中 20 个外显子的交替剪接产生普遍存在的组织- 特定的亚型，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、细胞凋亡、细胞骨架组织和 DNA 修复。 BIN1增加 据报道，在 LOAD 患者的大脑中存在 BIN1 的表达和可变剪接，但是如何 这些观察结果是否会导致 AD 风险增加尚不清楚。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 表达显着 和人类的大脑。通过生成少突胶质细胞特异性 Bin1 条件敲除 (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 人类老年斑附近的表达和 AD 转基因小鼠模型中淀粉样蛋白沉积物中 BIN1 的增加。 基于这些新发现，我们假设 BIN1 在成熟少突胶质细胞中发挥作用，并且 少突胶质细胞中 BIN1 表达和/或功能的改变在 AD 相关致病中发挥作用 以非细胞自主方式进行过程和神经变性。我们提出以下具体建议 旨在测试与 BIN1 在 AD 中的作用相关的新假设。该提案的具体目标是： 目标 1： 检验 AD 大脑中 BIN1 细胞表达和定位发生改变的假设。我们将调查 正常和患病人脑中的 BIN1 表达和交替剪接。我们将确定 通过分馏和共聚焦显微镜对 BIN1 进行亚细胞定位，并阐明 BIN1 的超微结构 使用免疫电子显微镜进行定位。目标 2：检验 BIN1 下调的假设 表达将减弱转基因小鼠中淀粉样蛋白和 tau 蛋白的病理学。我们将确定细胞类型是否 神经元或成熟少突胶质细胞中 BIN1 表达的特异性丧失将减弱 AD 相关性 转基因 AD 小鼠模型的神经病理学和行为缺陷。目标 3：检验假设 BIN1 在少突胶质细胞分化、存活和成熟以及体内髓鞘形成中发挥作用。我们 将利用 Bin1 cKO 小鼠模型和培养的少突胶质细胞来检验这一假设。这个提议是 及时、独特且高度创新。我们相信，我们的调查将揭示以下方面的重要见解： BIN1 在大脑中的功能，表征 AD 领域感兴趣的新型 Bin1 cKO 小鼠模型，建立 BIN1表达的减弱是否为疾病干预提供了新的策略，并奠定了 为表征与 AD 相关的 BIN1 功能变体奠定了基础，并指导未来的功能 该主要 LOAD 风险基因调控的生物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