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，最重要的迟发性阿尔茨海默病 (LOAD) 易感位点 GWAS，编码一种接头蛋白，可在内吞作用的背景下调节膜动力学神经递质囊泡释放 BIN1 可以直接结合 tau，这表明 BIN1 可能然而，我们和其他人未能找到与细胞质直接相关的证据。相反，令人信服的体外证据表明 BIN1·tau 与 AD 风险的相互作用。膜动力学限制致病性 tau 种子的摄取并影响 tau 的释放。 BIN1 可能调节 tau 病理学传播，但仍缺乏支持这一观点的体内证据。为了阐明 BIN1 功能与 AD 疾病风险的关系，有必要更好地了解 BIN1 在 tau 中的作用我们使用适当的动物模型对 tau 蛋白的发病机制和疾病进展进行了初步表征。 Bin1-cKO 小鼠的发病机制揭示了一幅复杂的图景：tau 转基因小鼠中 BIN1 表达缺失加剧脊髓中的 tau 蛋白病理，加速疾病进展，并导致过早死亡。有趣的是，BIN1 缺失还可以减轻脑萎缩并保护海马体免受神经炎症的影响，突触和神经元损失，从而极大地减少了特定区域的 tau 神经病理学。由于其直接的临床意义，研究结果需要扩展。我们的中心假设是 BIN1。由于 BIN1 是通过以区域特异性方式调节 tau 病理生理学来发挥其作为危险因素的功能。作为未来治疗的潜在目标，本次研究的总体目标是表征 BIN1 调制体内 tau 神经病理学的研究并获得对区域特异性 BIN1 功能的分子见解目标 1 的目标。是使用 CamK 和 PLP-CreERT 驱动程序生成细胞类型特异性诱导型 Bin1-cKO，表征 tau 使用体内纵向 MR 成像和详细的神经病理学研究发病机制，并检验以下假设： BIN1 表达调节特定大脑区域的 tau 神经病理学，Aim 2 研究将应用互补性。立体定位注射方法直接检验 BIN1 对细胞产生区域特异性影响的假设神经元到神经元 tau 蛋白通过突变 tau 模板相互作用传播或影响摄取和病理传播。目标 3 研究将通过批量和数字空间转录组策略进行分子分析，以绘制图谱细胞自主和非细胞自主疾病相关基因表达变化并阐明功能参与 BIN1 介导的区域特异性病理学调节的途径这一及时且独特的提议是。这项使用多只 Bin1-cKO 小鼠的研究代表了最直接的体内方法。严格研究 BIN1 参与 tau 神经病理学的生物学途径。拟议调查的成功完成将填补我们对 BIN1 理解的重大空白： LOAD 的风险因素并指导分子途径和致病性的未来功能表征受此主要 LOAD 风险基因调节的机制。