The role of Alzheimer's disease GWAS risk factor BIN1 in tau neuropathology and propagation in vivo

阿尔茨海默病 GWAS 危险因子 BIN1 在 tau 神经病理学和体内传播中的作用

基本信息

批准号：
10448676
负责人：
GOPAL THINAKARAN
金额：
$ 217.46万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10448676
关键词：
Adaptor Signaling Protein Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid deposition Animal Model Attenuated Binding Biological Brain Brain region Ca(2+)-Calmodulin Dependent Protein Kinase Cells Cessation of life Clinical Complex Cytosol Data Dementia Disease Disease Progression Endocytosis Foundations Functional disorder Future Gene Expression Goals Hippocampus (Brain)Human In Vitro Individual Injections Investigation Knockout Mice Late Onset Alzheimer Disease Link Magnetic Resonance Imaging Maps Mediating Membrane Memory impairment Modeling Molecular Molecular Analysis Mus Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neurotransmitters Oligodendroglia Outcome Pathogenesis Pathogenicity Pathology Pathway interactions Patients Performance Predisposition Recombinant adeno-associated virus (rAAV)Research Risk Factors Role Seeds Single Nucleotide Polymorphism Somatosensory Cortex Specificity Spinal Cord Suggestion Susceptibility Gene Synapses Tauopathies Testing Time Transgenic Mice Variant Vesicle Work cell type cerebral atrophy conditional knockout digital entorhinal cortex extracellular extracellular vesicles genome wide association study in vivo innovation insight neuroinflammation neuron loss neuropathology novel preservation prevent protein aggregation risk variant tau Proteins tau interaction tau mutation transcriptomics uptake vesicular release

项目摘要

BIN1, the most significant late-onset Alzheimer’s disease (LOAD) susceptibility locus identified via GWAS, encodes an adaptor protein that regulates membrane dynamics in the context of endocytosis and neurotransmitter vesicle release. BIN1 can directly bind to tau, leading to the suggestion that BIN1 might influence AD tangle pathology. However, we and others have failed to find evidence directly linking cytosolic BIN1·tau interaction to AD risk. In contrast, compelling in vitro evidence suggests that BIN1’s function in membrane dynamics limits pathogenic tau seed uptake and influences tau release. This indicates that neuronal BIN1 might regulate tau pathology propagation. In vivo evidence to support this notion is still lacking. In order to elucidate how BIN1 function relates to disease risk for AD, it is imperative to better understand BIN1’s role in tau pathogenesis and disease progression using appropriate animal models. Our preliminary characterization of tau pathogenesis in Bin1-cKO mice reveals a complex picture: the loss of BIN1 expression in tau transgenic mice exacerbated tau pathology in the spinal cord, accelerated disease progression, and caused early death. Intriguingly, BIN1 loss also attenuated brain atrophy and protected the hippocampus from neuroinflammation, synapse, and neuronal loss, thus, profoundly reducing tau neuropathology in select regions. These intriguing findings need to be extended because of their direct clinical implications. Our central hypothesis is that BIN1 exerts its function as a risk factor by modulating tau pathophysiology in a region-specific manner. Since BIN1 is a potential target for future therapies, the overall objective of this investigation is to characterize BIN1 modulation of tau neuropathology in vivo and gain molecular insights into region-specific BIN1 functions. The goal of Aim 1 is to generate cell-type-specific inducible Bin1-cKO using CamK- and PLP-CreERT-drivers, characterize tau pathogenesis using in vivo longitudinal MR imaging and detailed neuropathology and test the hypothesis that BIN1 expression modulates tau neuropathology in select brain regions. Aim 2 studies will apply complementary stereotaxic injection approaches to directly test the hypothesis that BIN1 exerts a region-specific influence on neuron-to-neuron tau spread or influences uptake and pathology propagation via mutant tau template interaction. Aim 3 studies will perform molecular analyses through bulk and digital spatial transcriptomic strategies to map cell-autonomous and non-cell-autonomous disease-related gene expression changes and elucidate functional pathways involved in BIN1-mediated region-specific pathology modulation. This timely and unique proposal is highly innovative. This investigation using multiple Bin1-cKO mice represents the most direct in vivo approach to rigorously investigate BIN1’s involvement in the biological pathways of tau neuropathology. We believe that the successful completion of the proposed investigation will fill significant gaps in our understanding of BIN1 as a risk factor for LOAD and guide future functional characterizations of molecular pathways and pathogenic mechanisms regulated by this major LOAD risk gene.

BIN1，最重要的晚期阿尔茨海默氏病（负载）易感性基因座通过 GWAS，编码一种衔接蛋白，该蛋白在内吞作用和神经递质囊泡释放。 BIN1可以直接与tau结合，导致建议BIN1可能影响广告缠结的病理。但是，我们和其他人未能找到直接连接胞质的证据 BIN1·Tau相互作用以与AD风险相互作用。相反，引人入胜的体外证据表明BIN1在膜动力学限制了致病性tau种子的吸收，并影响tau释放。这表明神经元 BIN1可能调节tau病理传播。在体内支持这一概念的证据仍然缺乏。为了阐明BIN1功能与AD疾病风险有关，必须更好地了解BIN1在TAU中的作用使用适当的动物模型的发病机理和疾病进展。我们对tau的初步特征 BIN1-CKO小鼠的发病机理揭示了一幅复杂的图片：Tau转基因小鼠中BIN1表达的丧失加剧了脊髓中的tau病理，加速了疾病进展，并引起早期死亡。有趣的是，BIN1丧失还减弱了脑萎缩，并保护了海马免受神经炎症的影响，突触和神经元丧失，因此，在某些区域中严重降低了tau神经病理学。这些有趣由于其直接的临床意义，需要扩展发现。我们的中心假设是Bin1 通过以特异性方式调节TAU病理生理学来发挥其作为危险因素的功能。因为BIN1是这项投资的总体目标是表征BIN1调制的一个潜在目标 Tau神经病理学中的体内并获得分子洞察到特定区域的BIN1功能。目标1的目标是使用CAMK-和PLP-CREERT-drivers生成细胞类型的诱导型BIN1-CKO，表征Tau 使用体内纵向MR成像和详细神经病理学的发病机理，并检验了以下假设。 BIN1表达调节特定大脑区域中的Tau神经病理学。 AIM 2研究将应用完件立体定义注射方法直接检验BIN1对区域特异性影响的假设神经到神经元tau传播或通过突变体tau模板相互作用影响摄取和病理传播。 AIM 3研究将通过批量和数字空间转录策略进行分子分析以绘制细胞自主和非细胞自主疾病相关的基因表达变化并阐明功能参与BIN1介导的区域特异性病理调节的途径。这个及时和独特的建议是高度创新。使用多个BIN1-CKO小鼠的投资代表了体内最直接的方法严格研究BIN1参与TAU神经病理学的生物学途径。我们相信拟议调查的成功完成将填补我们对BIN1的理解的重大空白负载和指导分子途径和致病性的未来功能特征的危险因素该主要负载风险基因调节的机制。