Oligodendrocyte precursor cells regulate white matter remodeling in vascular cognitive impairment and dementia

项目总结/摘要 皮质下缺血性血管性痴呆（SIVD）是最常见的血管性认知功能障碍 和痴呆（VCID）综合征。SIVD患者患有心室周围白色物质变性， 导致神经功能缺陷逐步发展，最终导致认知能力下降。之时尚 预计SIVD将随着人口老龄化而增加。然而，衰老的确切机制 影响SIVD病理学的药物仍然未知，可以支持SIVD中白色物质功能的药物 病人在等待。 SIVD主要由脑血管功能障碍引起，如长期低灌注。到目前为止，几乎 SIVD的所有机理研究都集中在血脑屏障（BBB）上。然而，BBB 功能障碍不是SIVD中唯一的致病事件。同样重要的是白色物质损伤 少突胶质细胞损伤和髓磷脂丢失与认知能力下降直接相关。对我们 缺乏对SIVD中少突胶质细胞机制的知识、分子和细胞研究。这 是我们试图填补的知识空白。 少突胶质细胞前体细胞（OPCs）是少突胶质细胞的主要来源， 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OPCs最活跃的发育过程中，一些OPCs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OPCs增殖， 分化为少突胶质细胞，为白色物质修复提供了重要途径。但 OPCs在成人脑中的作用大多是未知的，特别是在SIVD的条件下。所以我们 我提出假设，OPCs包括少突胶质细胞的关键来源，使受损的白色 重要的是启动恢复机制SIVD，但老化抑制这些补偿反应， OPCs通过下调支架蛋白AKAP 12。 我们将用三个目标来检验总体假设。在目标1中，我们将展示衰老的时空变化 SIVD-灌注不足小鼠中的OPC谱。在目标2中，我们将表明AKAP 12下调 抑制OPC分化。最后，在目标3中，我们将展示拯救OPC响应 阐明SIVD小鼠中的白色物质病理学。这项研究将提供新的见解的机制 年龄相关的OPC功能障碍通过该方法来解释白色物质病理学，并提供概念验证 AKAP 12可以成为SIVD的治疗靶点。

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.