Abstract
Introduction: Chronic cerebral hypoperfusion-derived brain damage contributes to the progression of vascular cognitive impairment and dementia (VCID). Cumulative evidence has shown that microRNAs (miRs) are emerging as novel therapeutic targets for CNS disorders. We have previously demonstrated that genetic manipulation of miR-15a/16-1 regulates neurovascular injury and functional outcomes in ischemic stroke. In this study, we sought to determine the role of miR-15a/16-1 in VCID. Hypothesis: Genetic deficiency of miR-15a/16-1 protects against white matter/grey matter injury and long-term neurobehavioral dysfunctions in VCID. Methods: Experimental VCID was induced in miR-15a/16-1 knockout (KO) mice and wild-type (WT) controls by asymmetric common carotid artery stenosis (ACAS) for 5 weeks. Neurobehavioral functions were evaluated by rotarod, adhesive tape removal, corner, water maze, and novel objective recognition tests. White matter injury was examined by diffusion tensor imaging, transmission electron microscopy, Luxol fast blue stain, and MBP/SMI32 double immunostaining. Grey matter injury was analyzed by Cresyl violet stain and NeuN immunostaining. The regulatory role of miR-15a/16-1 on AKT3 and IL-10RA were assessed by luciferase assay, qPCR, western blotting, and immunostaining. In addition, AKT3 and/or IL-10RA siRNA-loaded nanoparticles were intranasally delivered to miR-15a/16-1 KO mice with VCID. Results: Compared to WT controls, miR-15a/16-1 KO mice exhibited less cognitive and sensorimotor deficits following VCID. Genetic deficiency of miR-15a/16-1 in VCID mice also mitigated myelin degeneration, axonal injury, and neuronal loss. Mechanistically, miR-15a/16-1 binds to the 3’-UTR regions of AKT3 and IL-10RA. Genetic deletion of miR-15a/16-1 increased AKT3 and IL-10RA expression in VCID brains, and intranasal delivery of AKT3 and IL-10RA siRNA-loaded-nanoparticles partially reduced the brain protection and cognitive recovery in miR-15a/16-1 KO mice after VCID. Conclusions: MiR-15a/16-1-IL-10RA/AKT3 axis plays a critical role in regulating vascular brain damage and cognitive decline after VCID. Targeting miR-15a/16-1 is a novel miR-based therapeutic approach for the treatment of VCID.
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