Uncovering BIN1 functions in myelin-producing oligodendrocytes

项目摘要 髓鞘是轴突冲动快速传播和轴突的长期完整性和生存所必需的。大脑白色 物质改变是晚发性阿尔茨海默病大脑的常见早期特征，但这些改变的细胞基础 早在老年斑和含Tau的神经元缠结形成之前， 未开发的最近的大规模无偏转录组研究显示，在2000年， 阿尔茨海默病的早期阶段，这表明产生髓鞘的少突胶质细胞对AD的潜在贡献 发病机制有趣的是，晚发性阿尔茨海默病的第二个最普遍的遗传风险因素BIN 1是 主要由成熟的少突胶质细胞表达。然而，基本上对BIN 1函数一无所知， 在生理或病理生理条件下的少突胶质细胞。我们的初步数据表明，BIN 1蛋白是 分布在松散髓鞘的细胞质通道中的离散位置，并与磷酸化Tau相互作用 沿着轴突与早期Tau病理。因为少突胶质细胞利用细胞质通道将索马与远处的 包裹轴突并与轴突相互作用的外周过程，并且因为BIN 1在囊泡分选中起作用， 膜重塑和内吞，我们假设BIN 1在少突胶质细胞和轴突中起作用， 在神经元的通讯和髓鞘-轴突单位的完整性的长期维持中起重要作用。在R21提案中，我们将 确定（1）BIN 1在少突胶质细胞髓鞘形成和维持 使用少突胶质细胞特异性BIN 1条件性敲除小鼠的少突胶质细胞/髓鞘-轴突完整性;和（2） 使用转基因小鼠模型表达BIN 1的少突胶质细胞在调节轴突Tau病理中的作用 表达人类突变体Tau的基因了解BIN 1相关的细胞通路可能会提供新的见解， 这种危险因素如何与迟发性阿尔茨海默病的发作和/或进展以及相关的 痴呆症

PROJECT SUMMARY Myelin is essential to rapid axonal impulse propagation and long-term integrity and survival of axons. Cerebral white matter alterations are common early features in late-onset Alzheimer’s disease brains, yet the cellular basis for these changes, long before the formation of senile plaques and Tau-containing neurofibrillary tangles, remains largely unexplored. Large unbiased transcriptome studies recently revealed alterations in myelination and axonal integrity at the early stage of Alzheimer’s disease, suggesting potential contributions of myelin-producing oligodendrocytes to AD pathogenesis. Interestingly, the second most prevalent genetic risk factor for late-onset Alzheimer’s disease, BIN1, is primarily expressed by mature oligodendrocytes. However, essentially nothing is known about BIN1 functions in oligodendrocytes under physiological or pathophysiological conditions. Our preliminary data suggest that BIN1 protein is distributed at discrete locations in the cytoplasmic channels of uncompact myelin and interacts with phosphorylated Tau along axon with early Tau pathology. Because oligodendrocyte uses cytoplasmic channels to connect soma to distant peripheral processes that enwrap and interact with the axon, and because BIN1 plays a role in vesicle sorting, membrane remodeling and endocytosis, we hypothesize that BIN1 functions in oligodendrocyte and axon communication and in long-term maintenance of the integrity of the myelin-axon unit. In this R21 proposal, we will determine (1) the functional role of BIN1 in oligodendrocyte myelination and the maintenance of oligodendrocyte/myelin-axonal integrity using oligodendrocyte-specific BIN1 conditional knockout mice; and (2) the contribution of oligodendrocyte-expressing BIN1 in modulating axonal Tau pathology using a transgenic murine model that expresses human mutant Tau. Understanding BIN1-associated cellular pathways will likely provide new insights into how this risk factor might relate to the onset and/or progression of late-onset Alzheimer’s disease and related dementias.