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

• 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
• 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' s Disease; Alzheimer' 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

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，最重要的晚发性阿尔茨海默病(LOAD)易感基因座，通过 编码一种适配蛋白，在内吞作用和 神经递质囊泡释放。BIN1可以直接与tau结合，这导致了BIN1可能 影响AD的纠结病理。然而，我们和其他人未能找到直接与胞浆有关的证据 BIN1·tau交互作用对AD风险的影响。相比之下，令人信服的体外证据表明，BIN1的S在 膜动力学限制了病原性tau种子的吸收并影响tau的释放。这表明神经元 BIN1可能对tau的病理传播有调节作用。目前还缺乏支持这一观点的活体证据。为了 阐明BIN1功能与AD疾病风险的关系，有必要更好地理解BIN1在tau中的S角色 使用适当的动物模型研究发病机制和疾病进展。我们对tau的初步表征 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的表达缺失 加重了脊髓中的tau病理，加速了疾病的发展，并导致早期死亡。 有趣的是，BIN1的丢失还可以减轻大脑萎缩，保护海马体免受神经炎症的影响， 突触和神经元的丢失，因此，在选定的区域深刻地减少tau神经病理。这些耐人寻味 由于其直接的临床意义，这些发现需要扩展。我们的中心假设是BIN1 通过以区域特异性的方式调节tau的病理生理学，发挥其作为危险因子的作用。由于BIN1是 作为未来治疗的潜在靶点，这项研究的总体目标是表征BIN1的调节 在活体内研究tau神经病理，并获得对区域特定BIN1功能的分子洞察力。目标1的目标 是使用CaMK和PLP-CreERT驱动程序产生特定细胞类型的可诱导BIN1-CKO，表征tau 发病机制使用体内纵向磁共振成像和详细的神经病理，并验证假设 BIN1的表达调节特定脑区的tau神经病理。AIM 2研究将应用补充 立体定向注射方法直接检验BIN1对脑区特异性影响的假设 通过突变的tau模板相互作用，神经元到神经元的tau扩散或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，以绘制地图 细胞自主性和非细胞自主性疾病相关基因表达变化及功能研究 参与BIN1介导的区域特异性病理调控的通路。这一及时而独特的建议是 极具创新性。这项使用多只BIN1-CKO小鼠的研究代表了体内最直接的方法 严格研究BIN1‘S参与tau神经病理的生物学途径。我们相信 拟议调查的成功完成将填补我们对BIN1的理解上的重大空白 负载和引导分子通路和致病的未来功能特征的风险因素 受这一主要负荷风险基因调控的机制。