White Matter Injury and Repair in Vascular Cognitive Impairment and Dementia

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Vascular cognitive impairment and dementia (VCID) is the second most common type of dementia. No protective or disease-modifying strategies are available to reverse or halt VCID. A major feature of VCID is white matter pathology, including demyelination and a loss of myelin producing cells, which are highly correlated with cognitive deficits in the aged population. Oligodendrocyte precursor cell (OPC) differentiation occurs in white matter enriched areas upon chronic hypoxia but is insufficient for white matter repair. Thus, a legitimate strategy to improve functional outcomes in VCID is to enhance white matter integrity by protecting oligodendrocytes and by promoting oligodendrocyte regeneration. Adiponectin, the most abundant adipokine in the blood, plays a crucial role in CNS pathologies. We have reported that adiponectin is important for cognitive function and reduces hippocampal neuronal loss in the asymmetric common carotid artery stenosis (ACAS) mouse model of VCID. However, the effects of adiponectin on white matter integrity after VCID are unknown. To fill this important gap, we recently evaluated the functional impact of adiponectin on white matter components after ACAS in young mice. Our pilot data show that adiponectin deficiency reduces white matter integrity and impairs axonal conduction 42d after ACAS. Adiponectin knockout (KO) mice display greater oligodendrocyte loss and less oligodendrocyte regeneration. In contrast, treatment with adipoRon, a small-molecule agonist of adiponectin receptors, improves long-term white matter integrity and leads to superior cognitive functions up to 42d after ACAS. We observed that adiponectin receptor 1 (adipoR1) is highly expressed on oligodendrocytes and microglia in vivo. In vitro data further suggest that adipoRon protects cultured oligodendrocytes against oxygen/glucose deprivation through AMPK activation. AdipoRon also enhances microglial phagocytosis and promotes the oligodendrogenic capacities of microglia. Based on these promising data, we will test the new hypothesis that adiponectin promotes structural and functional white matter integrity and improves neurological function in chronic cerebral hypoperfusion- induced VCID by dual mechanisms: 1) enhancing oligodendrocyte survival through AMPK activation, and 2) promoting a reparative microglial phenotype with high oligodendrogenic capacities. Three Specific Aims will be tested. Aim 1: Test if adiponectin protects oligodendrocytes in an AMPK-dependent manner to improve white matter integrity after ACAS. Aim 2: Test if adiponectin shifts microglia toward a reparative phenotype that enhances OPC differentiation after ACAS. Aim 3: Test if adipoRon treatment enhances white matter integrity and improves long-term cognitive functions after ACAS in aged mice of both sexes. These studies will shed light on adiponectin as a key mediator to improve white matter integrity in VCID. Positive outcomes would also hasten the development of adipoRon as a clinical treatment in elderly men and women with VCID.