Unlocking BIN1 function in oligodendrocytes and support of axon integrity

解锁少突胶质细胞中的 BIN1 功能并支持轴突完整性

基本信息

批准号：
10901005
负责人：
JIANRONG LI
金额：
$ 46.65万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10901005
关键词：
Acceleration Adaptor Signaling Protein Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Axon Brain C-terminal Cells Central Nervous System Cerebrum Clinical Communication Coupling Cytoplasm Data Demyelinations Development Disease Disease Progression Distant Endosomes Etiology Exhibits Functional disorder Genetically Engineered Mouse Human Impaired cognition Individual Knockout Mice Late Effects Late Onset Alzheimer Disease Location Maintenance Membrane Memory Memory impairment Microglia Mus Mutant Strains Mice Mutation Myelin Myelin Sheath Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oligodendroglia Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Performance Peripheral Persons Physiological Play Prevalence Process Protein Isoforms Proteins Recycling Research Proposals Risk Risk Factors Role SH3 Domains Senile Plaques Single Nucleotide Polymorphism Societies System Tauopathies Testing Tissues Transgenic Mice Travel Variant Vesicle age related axon injury axonal degeneration axonopathy conditional knockout conditional mutant effective therapy genetic risk factor gray matter insight knock-down loss of function mutation membrane model mouse model mutant myelination neglect neurobehavior neuroimaging neuronal cell body neuronal survival normal aging novel tau Proteins tau mutation trafficking transcriptome transcriptomics white matter

项目摘要

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 (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.

项目概要：髓磷脂对于轴突冲动的快速传播和大脑轴突的长期完整性和存活至关重要。白质改变是晚发性阿尔茨海默病 (AD) 大脑的常见早期特征，但这些变化的细胞基础早在老年斑和含 Tau 的神经原纤维形成之前最近，大量无偏见的转录组研究揭示了缠结的变化。阿尔茨海默病早期阶段的髓鞘形成和轴突完整性，表明 AD 发病机制中产生髓磷脂的少突胶质细胞。迟发性阿尔茨海默病的因子 BIN1 主要由成熟的少突胶质细胞表达。关于 BIN1 在生理或病理生理条件下在少突胶质细胞中的功能知之甚少。我们的初步数据表明 BIN1 蛋白分布在细胞质通道的离散位置此外，成人大脑成熟少突胶质细胞中 Bin1 的特异性缺失。在没有明显脱髓鞘的情况下，导致轴突完整性的年龄依赖性破坏和退化。因为少突胶质细胞使用细胞质通道将体细胞连接到远处的外周过程，包裹轴突并与其相互作用，并且因为 BIN1 在囊泡动力学和膜中发挥作用重塑，我们追求 BIN1 在少突胶质细胞/轴突通讯中的功能，以及丢失或少突胶质细胞-BIN1轴功能障碍会加剧与年龄相关的髓磷脂/轴突衰退和Tau蛋白在本研究提案中，我们将使用少突胶质细胞特异性 BIN1 条件敲除小鼠和携带迟发性 AD BIN1 变体的突变小鼠研究少突胶质细胞-BIN1 在衰老和 AD 的 Tau 病小鼠模型中的髓磷脂/轴突完整性。生理和病理生理途径可能会为该危险因素如何可能提供新的见解迟发性阿尔茨海默病和相关痴呆症的发病和/或进展。