White Matter Restoration in Vascular Cognitive Impairment and dementia

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Abstract Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia after Alzheimer’s disease. Although the causes for VCID are not clear, increasing evidence suggests cerebral hypoperfusion is the dominant pathogenic process. Cerebral hypoperfusion causes the death of oligodendrocytes, the only myelin (the key component in nerve fiber) producing cells in CNS, leading to white matter injury (WMI) which is closely related to VCID. Thus, interventions targeted at WMI—an area that remains poorly understood—may provide a new therapy for both WMI and VCID. We have successfully reprogrammed reactive astrocytes into oligodendrocyte progenitor cells (iOPCs) by three transcription factors (named SOA) in ischemic brain. Reprogrammed OPCs can proliferate/differentiate into mature oligodendrocytes, repair WMI and improve sensorimotor and cognitive function. Thus, we intend to test the therapeutic potential of reprogrammed oligodendrocytes in WM restoration and in cognitive dysfunction/memory loss in mouse models that mimic common carotid artery (CCA) hypoperfusion caused by arteriosclerotic CCA stenosis. The central hypothesis is that in situ reprogramming of activated astrocytes into oligodendrocytes can restore white matter integrity and improve long- term cognitive recovery in VCID models induced by CCA hypoperfusion. The following three Aims are proposed: Aim 1 will characterize the maturity of reprogrammed OPCs and their role in WM restoration in CCA hypoperfusion models in both genders and the underlaying mechanism whether reprogrammed OPCs enhance WM restoration by enhancing axonal remyelination and stimulating axonal sprouting. Aim 2 will test if iOPCs enhance long-term sensorimotor and cognitive function as well as axonal function in the needle CCA hypoperfusion model in young and aged mice. Aim 3 will test if ICV administration of recombinant SOA pool protein can reprogram reactive astrocytes into oligodendrocytes, restore WM integrity, and improve cognitive recovery in a needle CCA hypoperfusion model. The proposed study is the first to reprogram astrocytes in situ into viable oligodendrocytes and will provide a novel therapeutic approach for WMI and VCID as well other CNS diseases that involve WMI.