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

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.

Grant Number: 5R01NS113556-05
NIH Institute/Center: NIH
Principal Investigator: Ken Arai