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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\u201015a\/16\u20101 in VCID. It is found that miR\u201015a\/16\u20101 knockout (KO) mice exhibit less cognitive and sensorimotor deficits following VCID. Genetic deficiency of miR\u201015a\/16\u20101 in VCID mice also mitigate myelin degeneration, axonal injury, and neuronal loss. Mechanistically, miR\u201015a\/16\u20101 binds to the 3\u2019\u2010UTR of AKT3 and IL\u201010RA. Genetic deletion of miR\u201015a\/16\u20101 increases AKT3 and IL\u201010RA expression in VCID brains, and intranasal delivery of AKT3 and IL\u201010RA siRNA\u2010loaded nanoparticles partially reduce brain protection and cognitive recovery in miR\u201015a\/16\u20101 KO mice after VCID. In conclusion, the miR\u201015a\/16\u20101\u2010IL\/10RA\/AKT3 axis plays a critical role in regulating vascular brain damage and cognitive decline after VCID. Targeting miR\u201015a\/16\u20101 is a novel therapeutic approach for the treatment of VCID.<\/jats:p>","DOI":"10.1002\/advs.202104986","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T08:15:43Z","timestamp":1649664943000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Genetic Deficiency of MicroRNA\u201015a\/16\u20101 Confers Resistance to Neuropathological Damage and Cognitive Dysfunction in Experimental Vascular Cognitive Impairment and Dementia"],"prefix":"10.1002","volume":"9","author":[{"given":"Chao","family":"Zhou","sequence":"first","affiliation":[{"name":"Pittsburgh Institute of Brain Disorders &amp; Recovery Department of Neurology University of Pittsburgh School of Medicine  Pittsburgh PA 15213 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Sun","sequence":"additional","affiliation":[{"name":"Pittsburgh Institute of Brain Disorders &amp; Recovery Department of Neurology University of Pittsburgh School of Medicine  Pittsburgh PA 15213 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Pittsburgh Institute of Brain Disorders &amp; Recovery Department of Neurology University of Pittsburgh School of Medicine  Pittsburgh PA 15213 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuang","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Pharmacogenetics University of Pittsburgh School of Pharmacy  Pittsburgh PA 15213 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixian","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Pharmacogenetics University of Pittsburgh School of Pharmacy  Pittsburgh PA 15213 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milton H.","family":"Hamblin","sequence":"additional","affiliation":[{"name":"Tulane University Health Sciences Center Tulane University  New Orleans LA 70112 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley","family":"Foley","sequence":"additional","affiliation":[{"name":"Animal Imaging Center Department of Neurobiology University of Pittsburgh School of Medicine  Pittsburgh PA 15203 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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