Unlocking BIN1 function in oligodendrocytes and support of axon integrity

Texas A&M Agrilife Research, College Station TX

Investigators

Abstract

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 (AD) 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, little 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 regions. Moreover, specific deletion of Bin1 in mature oligodendrocytes in adult brain results in age-dependent disruption of axon integrity and degeneration in the absence of overt demyelination. 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 dynamics and membrane remodeling, we hypothesize that BIN1 functions in oligodendrocyte/axon communication and that loss or dysfunction of the oligodendrocyte-BIN1 axis aggravates age-associated myelin/axon decay and Tau pathology. In this research proposal, we will use oligodendrocyte-specific BIN1 conditional knockout mice and mutant mice carrying a late-onset the AD BIN1 variant to investigate the role of oligodendrocyte-BIN1 in myelin/axonal integrity in aging and in a Tauopathy mouse model of AD. Understanding BIN1-associated physiological and pathophysiological 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.