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Genetic Deficiency of MicroRNA-15a/16-1 Confers Resistance to Neuropathological Damage and Cognitive Dysfunction in
Chao Zhou1, Ping Sun1, Yang Xu1
1Pittsburgh Institute of Brain Disorders & Recovery, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
Abstract:
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. In this study, it is sought to determine the regulatory role of miR-15a/16-1 in VCID. It is found that miR-15a/16-1 knockout (KO) mice exhibit less cognitive and sensorimotor deficits following VCID. Genetic deficiency of miR-15a/16-1 in VCID mice also mitigate myelin degeneration, axonal injury, and neuronal loss. Mechanistically, miR-15a/16-1 binds to the 3'-UTR of AKT3 and IL-10RA. Genetic deletion of miR-15a/16-1 increases AKT3 and IL-10RA expression in VCID brains, and intranasal delivery of AKT3 and IL-10RA siRNA-loaded nanoparticles partially reduce brain protection and cognitive recovery in miR-15a/16-1 KO mice after VCID. In conclusion, the 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 therapeutic approach for the treatment of VCID.
Insights
Targeting microRNA-15a/16-1 (miR-15a/16-1) shows promise for treating vascular cognitive impairment and dementia (VCID). Inhibiting miR-15a/16-1 in mice reduced brain damage and cognitive deficits associated with VCID.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Chronic cerebral hypoperfusion causes brain damage, progressing vascular cognitive impairment and dementia (VCID).
- MicroRNAs (miRs) are increasingly recognized as potential therapeutic targets for central nervous system (CNS) disorders.
Purpose of the Study:
- To investigate the regulatory role of miR-15a/16-1 in the context of VCID.
- To elucidate the molecular mechanisms underlying miR-15a/16-1's function in VCID.
Main Methods:
- Utilized miR-15a/16-1 knockout (KO) mice to assess cognitive and sensorimotor functions after inducing VCID.
- Analyzed myelin integrity, axonal injury, and neuronal loss in VCID mice with and without miR-15a/16-1.
- Investigated the binding of miR-15a/16-1 to AKT3 and IL-10RA 3'-UTRs.
- Employed intranasal delivery of siRNA-loaded nanoparticles targeting AKT3 and IL-10RA.
Main Results:
- miR-15a/16-1 KO mice exhibited significantly reduced cognitive and sensorimotor deficits following VCID.
- Genetic deficiency of miR-15a/16-1 mitigated myelin degeneration, axonal injury, and neuronal loss in VCID brains.
- Deletion of miR-15a/16-1 increased AKT3 and IL-10RA expression; nanoparticle delivery partially reversed these effects.
Conclusions:
- The miR-15a/16-1-IL-10RA-AKT3 axis is crucial in regulating vascular brain damage and cognitive decline in VCID.
- Targeting miR-15a/16-1 presents a novel therapeutic strategy for treating VCID.
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