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.

PROJECT NARRATIVE Subcortical ischemic vascular dementia (SIVD) is the most common form of vascular cognitive impairment and dementia syndrome. While the prevalence of SIVD is expected to increase as the population ages, the precise mechanisms by which aging affects SIVD pathology is still unknown. In this study, we will test our hypothesis that oligodendrocyte precursor cells (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.