Adiponectin Fortifies White Matter After Chronic Hypoperfusion-Induced Vascular Dementia.

Abstract

Vascular cognitive impairment and dementia is characterized by profound demyelination of white matter and the loss of myelin-producing oligodendrocytes. Clinical reports reveal negative correlations between plasma levels of adiponectin, the most abundant adipokine, and the severity of white matter lesions and cognitive impairments. Therefore, this study evaluated the effects of adiponectin and adipoRon, a small-molecule agonist of adiponectin receptors, on white matter integrity after chronic hypoperfusion-induced vascular cognitive impairment and dementia. Male C57BL/6 wild-type, adiponectin knockout, and wild-type microglia-depleted (PLX5622-treated) mice were subjected to asymmetrical common carotid artery stenosis to model vascular cognitive impairment and dementia. White matter integrity was measured by immunohistochemistry, transmission electron microscopy, electrophysiology, and ex vivo diffusion tensor imaging. Cognitive functions were evaluated by Morris water maze, Y maze, and passive avoidance tests. A model of lysophosphatidylcholine/LPC (lysolecithin)-mediated demyelination using ex vivo organotypic cerebellar slice cultures was used to assess white matter repair. Primary microglia and oligodendrocytes were prepared for in vitro studies. Statistical tests (<i>t</i> test or ANOVA) were based on the group numbers, types of variables, and data structure. Adiponectin deficiency worsened white matter lesions and impaired axonal conduction compared with wild-type mice 42 days after asymmetrical common carotid artery stenosis. Conversely, adipoRon improved white matter integrity for the long term in both young and aged mice, consistent with their superior cognitive functions after asymmetrical common carotid artery stenosis. Adiponectin and adipoRon directly protected primary oligodendrocytes against oxygen/glucose deprivation, enhanced microglial engulfment of myelin debris, and promoted oligodendrogenic capacities of microglia in vitro. AdipoRon treatment enhanced microglial engulfment of damaged myelin after asymmetrical common carotid artery stenosis and boosted oligodendrocyte regeneration and white matter integrity in a microglia-dependent manner. Adiponectin strengthens white matter integrity in chronic hypoperfusion-induced vascular cognitive impairment and dementia, providing a novel therapeutic target. Adiponectin may exert dual mechanistic effects by enhancing oligodendrocyte survival and promoting a reparative microglial phenotype.