Oligodendrocyte Precursor Cells Regulate White Matter Remodeling in Vascular Cognitive Impairment and Dementia

少突胶质细胞前体细胞调节血管认知障碍和痴呆中的白质重塑

基本信息

批准号：
10650804
负责人：
Ken Arai
金额：
$ 45.85万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10650804
关键词：
Adult Affect Age Aging Axon Blood - brain barrier anatomy Blood brain barrier dysfunction Brain Cell Count Cell Differentiation process Cell Lineage Cell Proliferation Cell Survival Cells Cerebrovascular Disorders Cerebrum Cognitive Complementary DNA Data Demyelinations Development Disease Down-Regulation Endothelial Cells Endothelium Event Exhibits Female Functional disorder Gravin Growth Factor Impaired cognition In Vitro Injections Injury Investigation Knockout Mice Knowledge Link Maps Modeling Molecular Mus Myelin Natural regeneration Neurologic Deficit Oligodendroglia Outcome Pathogenicity Pathology Patients Pattern Pericytes Pharmaceutical Preparations Population Prevalence Proliferating Recovery Regenerative response Regulation Research Residual state Role Scaffolding Protein Signal Transduction Source Supporting Cell Syndrome Testing Transfection Tretinoin Undifferentiated Up-Regulation Vascular Dementia Ventricular age related brain endothelial cell cerebral hypoperfusion cognitive function experimental study genetic approach hypoperfusion improved in vivo insight male middle age mouse model myelination novel oligodendrocyte lineage oligodendrocyte precursor pharmacologic precursor cell repaired response spatiotemporal subcortical ischemic vascular disease therapeutic target vascular cognitive impairment and dementia white matter white matter damage white matter injury

项目摘要

PROJECT SUMMARY/ABSTRACT Subcortical ischemic vascular dementia (SIVD) is the most common form of vascular cognitive impairment and dementia (VCID) syndrome. SIVD patients suffer from peri-ventricular white matter degeneration that leads to stepwise development of neurological deficits, culminating in cognitive decline. The prevalence of SIVD is expected to increase as the population ages. However, the precise mechanisms by which aging affects SIVD pathology is still unknown, and medications that can support white matter function in SIVD patients are awaited. SIVD is primarily caused by cerebrovascular dysfunction, such as prolonged hypoperfusion. To date, almost all of the mechanistic research in SIVD has focused on the blood-brain barrier (BBB). However, BBB dysfunction is not the only pathogenic event in SIVD. Equally important is the white matter injury manifested as oligodendrocyte damage and myelin loss that should be directly linked to cognitive decline. To our knowledge, molecular and cellular investigations into oligodendrocyte mechanisms in SIVD are lacking. This is the major gap in knowledge that we seek to fill. Oligodendrocyte precursor cells (OPCs) comprise the main source of oligodendrocytes, and proper regulation of OPC-to-oligodendrocyte differentiation is necessary to maintain effective myelination and axon function. After development during which OPCs are most active, some OPCs remain in an undifferentiated state in the adult brain. In the setting of oligodendrocyte injury and loss, these residual OPCs proliferate and differentiate into oligodendrocytes, providing an important avenue for white matter repair. However, the roles of OPCs in adult brain are mostly unknown, especially under the conditions of SIVD. Therefore, we propose the hypothesis that OPCs comprise a key source of oligodendrocytes that allow damaged white matter to initiate recovery mechanisms in SIVD, but aging dampens these compensative responses in OPCs via downregulation of a scaffolding protein AKAP12. We will test the overall hypothesis with 3 aims. In Aim 1, we will show that aging changes spatiotemporal OPC profiles in SIVD-hypoperfusion mice. In Aim 2, we will show that AKAP12 downregulation suppresses OPC differentiation. And finally, in Aim 3, we will show that rescuing OPC responses alleviates white matter pathology in SIVD mice. This study will provide novel insight into the mechanisms by which age-related OPC dysfunction worsens white matter pathology, and provide proof-of-concept that AKAP12 can be a therapeutic target for SIVD.

项目摘要/摘要皮层缺血性血管痴呆（SIVD）是血管认知障碍的最常见形式和痴呆症（VCID）综合征。 SIVD患者患有腹膜周期白质变性导致神经缺陷的逐步发展，最终导致认知能力下降。流行率随着人口年龄的增长，SIVD预计将增加。但是，衰老的确切机制影响SIVD病理仍然未知，并且可以支持SIVD中白质功能的药物等待患者。 SIVD主要是由脑血管功能障碍引起的，例如长期灌注不足。迄今为止，几乎 SIVD中的所有机械研究都集中在血脑屏障（BBB）上。但是，BBB 功能障碍不是SIVD中唯一的致病事件。同样重要的是表现出的白质伤害由于少突胶质细胞损伤和髓磷脂损失应直接与认知下降有关。向我们缺乏对SIVD中少突胶质细胞机制的知识，分子和细胞研究。这是我们寻求填补的知识的主要差距。少突胶质细胞前体细胞（OPC）构成了少突胶质细胞的主要来源，并且适当 OPC到寡聚胶质细胞分化的调节对于维持有效的髓鞘形成和轴突是必要的功能。开发后，OPC最活跃，一些OPC仍在未分化的在成人大脑中陈述。在少突胶质细胞损伤和损失的情况下，这些残留的OPC扩散和分化为少突胶质细胞，为白质维修提供了重要的途径。但是， OPC在成人大脑中的作用大多是未知的，尤其是在SIVD条件下。因此，我们提出这样的假设，即OPC构成了允许损坏的白色的少突胶质细胞的关键来源在SIVD中启动恢复机制的问题，但老化会削弱这些补偿性反应 OPC通过下调脚手架蛋白AKAP12。我们将以3个目标检验总体假设。在AIM 1中，我们将表明衰老变化时空变化 SIVD-杂化小鼠中的OPC轮廓。在AIM 2中，我们将证明AKAP12下调抑制OPC分化。最后，在AIM 3中，我们将表明拯救OPC回复减轻SIVD小鼠中的白质病理学。这项研究将为机制提供新的见解与年龄相关的OPC功能障碍在哪种情况下使白质病理恶化，并提供了概念证明 AKAP12可以是SIVD的治疗靶标。