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

BIN 1是最重要的迟发性阿尔茨海默病（LOAD）易感基因，通过 GWAS编码一种衔接蛋白，在胞吞作用中调节膜动力学， 神经递质囊泡释放。BIN 1可以直接与tau蛋白结合，这表明BIN 1可能与tau蛋白结合。 影响AD缠结病理。然而，我们和其他人未能找到直接将细胞质 BIN 1·tau与AD风险的相互作用。相反，令人信服的体外证据表明，BIN 1的功能， 膜动力学限制了致病性tau种子摄取并影响tau释放。这表明神经元 BIN 1可能调控tau蛋白的病理增殖。支持这一观点的体内证据仍然缺乏。为了 为了阐明BIN 1功能如何与AD的疾病风险相关，必须更好地了解BIN 1在tau蛋白中的作用， 使用适当的动物模型研究发病机制和疾病进展。我们对tau蛋白的初步鉴定 Bin 1-cKO小鼠的发病机制揭示了一个复杂的画面：在tau转基因小鼠中BIN 1表达的丧失 加剧了脊髓中的tau病理学，加速了疾病进展，并导致早期死亡。 有趣的是，BIN 1的缺失也减轻了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，从而显著降低选择区域中的tau神经病理学。这些有趣 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BIN 1 通过以区域特异性方式调节tau病理生理学来发挥其作为风险因素的功能。由于BIN 1是 作为未来治疗的潜在靶点，本研究的总体目标是表征BIN 1调节 tau神经病理学的研究，并获得对区域特异性BIN 1功能的分子见解。Aim 1的目标 使用CamK-和PLP-CreERT-驱动器产生细胞类型特异性诱导型Bin 1-cKO，表征tau 使用体内纵向MR成像和详细的神经病理学来研究发病机制，并检验以下假设： BIN 1表达调节选定脑区域中的tau神经病理学。目标2研究将采用补充 立体定位注射方法，以直接测试BIN 1发挥区域特异性影响的假设， 神经元-神经元tau扩散或通过突变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组策略进行分子分析， 细胞自主性和非细胞自主性疾病相关基因表达的变化，并阐明功能 参与BIN 1介导的区域特异性病理学调节的途径。这一及时而独特的建议是 极具创新性。使用多只Bin 1-cKO小鼠的这项研究代表了最直接的体内方法 严格调查BIN 1参与tau神经病理学的生物学途径。我们认为 成功完成拟议的调查将填补我们对BIN 1的理解中的重大空白， LOAD的风险因素，并指导未来的分子途径和致病性 这一主要的LOAD风险基因调控的机制。

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.