Uncovering BIN1 functions in myelin-producing oligodendrocytes

揭示 BIN1 在产生髓磷脂的少突胶质细胞中的功能

基本信息

批准号：
10214226
负责人：
JIANRONG LI
金额：
$ 40.25万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214226
关键词：
Adaptor Signaling Protein Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Antibodies Apolipoprotein E Axon BIN1 gene Binding Biological Brain C-terminal Cell membrane Cells Cerebrum Clinical Communication Data Disease Disease Progression Distant Endocytosis Etiology Exhibits Genetic Polymorphism Genetic Transcription Genetically Engineered Mouse Health Human Impaired cognition In Vitro Individual Knockout Mice Late Onset Alzheimer Disease Location Maintenance Mediating Membrane Memory impairment Microglia Myelin Myelin Sheath Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neurons Oligodendroglia Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Peripheral Physiological Play Prevalence Process Protein Isoforms Proteins Research Risk Risk Factors Rodent Role Senile Plaques Societies Sorting - Cell Movement Synapses Tauopathies Testing Time Tissues Transgenic Organisms Travel Variant Vesicle age related base conditional knockout effective therapy extracellular extracellular vesicles genetic risk factor gray matter high risk in vivo insight membrane model mouse model myelination neglect neuroimaging neuronal cell body novel oligodendrocyte myelination postnatal period repaired tau Proteins tau mutation tau-1 transcriptome transcriptomics uptake vesicle transport 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 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.

项目概要髓磷脂对于轴突冲动的快速传播以及脑白轴突的长期完整性和存活至关重要。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 的神经原纤维缠结形成之前，这些变化就在很大程度上仍然存在未经探索的大型无偏见转录组研究最近揭示了髓鞘形成和轴突完整性的改变。阿尔茨海默病的早期阶段，表明产生髓磷脂的少突胶质细胞对阿尔茨海默病有潜在贡献提示，迟发性阿尔茨海默病的第二个最常见的遗传风险因素是 BIN1。主要由成熟的少突胶质细胞表达，但是，对于 BIN1 的功能尚不清楚。我们的初步数据表明，BIN1 蛋白在生理或病理生理条件下是少突胶质细胞。分布在松散髓磷脂细胞质通道的离散位置，并与磷酸化 Tau 相互作用因为少突胶质细胞使用细胞质通道将体细胞连接到远处。包裹轴突并与轴突相互作用的外周过程，并且由于 BIN1 在囊泡分选中发挥作用，膜重塑和内吞作用，我们勇敢地说BIN1在少突胶质细胞和轴突中发挥作用沟通和长期维持髓磷脂轴突单位的完整性。在这个 R21 提案中，我们将。确定 (1) BIN1 在少突胶质细胞髓鞘形成和维持中的功能作用使用少突胶质细胞特异性 BIN1 条件敲除小鼠的少突胶质细胞/髓磷脂轴突完整性；以及（2）使用转基因小鼠模型表达少突胶质细胞 BIN1 在调节轴突 Tau 病理学中的贡献了解 BIN1 相关细胞通路可能会提供新的见解。该风险因素如何与迟发性阿尔茨海默病及相关疾病的发病和/或进展相关痴呆症。