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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：
10558808
负责人：
Ken Arai
金额：
$ 5.88万
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/10558808
关键词：
AKAP12 gene Adult Affect Age Aging Axon Blood - brain barrier anatomy 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 Financial compensation Functional disorder 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 Pharmacology 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 age related base 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 precursor cell repaired response spatiotemporal 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.

项目概要/摘要皮质下缺血性血管性痴呆（SIVD）是血管性认知障碍的最常见形式和痴呆（VCID）综合征。 SIVD 患者患有脑室周围白质变性，导致神经功能缺陷逐步发展，最终导致认知能力下降。患病率随着人口老龄化，SIVD 预计会增加。然而，衰老的确切机制影响 SIVD 病理学的情况仍不清楚，可以支持 SIVD 中白质功能的药物患者正在等待。 SIVD 主要由脑血管功能障碍引起，例如长期低灌注。迄今为止，几乎 SIVD 的所有机制研究都集中在血脑屏障 (BBB) 上。然而，BBB 功能障碍并不是 SIVD 的唯一致病事件。同样重要的是白质损伤的表现少突胶质细胞损伤和髓鞘质丧失应该与认知能力下降直接相关。致我们的缺乏关于 SIVD 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主要知识空白。少突胶质细胞前体细胞（OPC）是少突胶质细胞的主要来源，适当的 OPC 向少突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。在 OPC 最活跃的发育过程后，一些 OPC 仍处于未分化状态成人大脑中的状态。在少突胶质细胞损伤和丢失的情况下，这些残留的 OPC 会增殖并分化为少突胶质细胞，为白质修复提供重要途径。然而， OPCs 在成人大脑中的作用大多是未知的，特别是在 SIVD 条件下。因此，我们提出这样的假设：OPC 是少突胶质细胞的一个关键来源，使受损的白细胞 SIVD 中启动恢复机制很重要，但衰老会抑制这些补偿反应 OPCs 通过支架蛋白 AKAP12 的下调。我们将通过 3 个目标来检验总体假设。在目标 1 中，我们将展示衰老在时空上的变化 SIVD 低灌注小鼠的 OPC 概况。在目标 2 中，我们将证明 AKAP12 下调抑制 OPC 分化。最后，在目标 3 中，我们将展示拯救 OPC 响应减轻 SIVD 小鼠的白质病理。这项研究将为机制提供新的见解年龄相关的 OPC 功能障碍使白质病理恶化，并提供了概念验证 AKAP12 可以成为 SIVD 的治疗靶点。