Uncovering BIN1 functions in myelin-producing oligodendrocytes

点击翻译按钮获取中文摘要

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.