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

项目摘要/摘要 皮质下缺血性血管性痴呆(SIVD)是最常见的血管认知功能障碍 和痴呆(VCID)综合征。SIVD患者患有脑室周围白质变性， 导致神经缺陷的逐步发展，最终导致认知能力下降。疾病的流行 随着人口老龄化，SIVD预计将增加。然而，衰老的确切机制 影响SIVD的病理机制尚不清楚，可以支持SIVD白质功能的药物 病人在等着呢。 SIVD主要是由脑血管功能障碍引起的，如长期低灌注量。到目前为止，几乎 SIVD的发病机制研究主要集中在血脑屏障(BBB)方面。然而，BBB 功能障碍并不是SIVD的唯一致病事件。同样重要的是表现出的脑白质损伤 由于少突胶质细胞损伤和髓鞘丢失，应该与认知能力下降有直接联系。致我们的 关于少突胶质细胞在SIVD发病机制方面的知识、分子和细胞研究尚缺乏。这 是我们寻求填补的知识的主要缺口。 少突胶质前体细胞(OPC)是少突胶质细胞的主要来源， 调控OPC向少突胶质细胞分化对于维持有效的髓鞘形成和轴突是必要的 功能。在OPC最活跃的发展过程中，一些OPC仍处于未分化状态 在成人大脑中的状态。在少突胶质细胞损伤和丢失的背景下，这些残留的OPC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， OPC在成人脑中的作用大多尚不清楚，尤其是在SIVD的情况下。因此，我们 提出一种假设，即OPC包括一个关键的少突胶质细胞来源，允许受损的白色细胞 启动SIVD恢复机制的物质，但衰老抑制了这些代偿性反应 OPC通过下调支架蛋白AKAP12。 我们将用三个目标来检验整个假设。在目标1中，我们将展示衰老的时空变化 SIVD低灌流小鼠的OPC谱。在目标2中，我们将展示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小鼠的脑白质病理。这项研究将为了解这一机制提供新的见解。 与年龄相关的OPC功能障碍会恶化脑白质病理，并提供概念验证 AKAP12可作为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.