MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Abstract

Chronic cerebral hypoperfusion (CCH) characterized by global cerebral ischemia is an important risk factor contributing to the development of dementia. MicroRNAs (miRNAs) play important roles in the cellular adaptation to long-term ischemia/hypoxia by turning off or on the expression of target genes. MiR-181c is widely expressed in the nervous system, and tripartite motif 2 (TRIM2) is one of its target genes. In this work, we had identified that progressive spatial memory deficiency was induced in the bilateral common carotid artery occlusion (2-VO) rat models. Meanwhile, inhibition of miR-181c expression and upregulation of TRIM2 in the hippocampus of 2-VO rats were found accompanying with reduction in the dendritic branching and dendrite spine density of the hippocampal neurons. Viral vector-mediated miR-181c delivery might improve the cognitive deficiency via TRIM2 on neurofilament light (NF-L) ubiquitination resulting in remodeling of the hippocampal neurons as well as increase in N-methyl-D-aspartate receptor 1 (NR1) subunit cell surface expression. Meanwhile, miR-181c might rescue the cellular activity from ischemia/hypoxia. These results indicated a novel miRNA-mediated mechanism involving miR-181c and TRIM2 in the cognitive impairment induced by CCH and provided a rationale for the development of miRNA-based strategies for prevention of dementia.

Adenosine A2A Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury

“…IL-1β receptor inhibitors and IL-1β knockout mice block the IL-1β signaling pathway, thereby inducing oligodendrocyte premature cell migration to the periphery of the corpus callosum, and avoiding white matter damage and reversing chronic hypoperfusion-induced cognitive dysfunction by improving the local inflammatory environment [26]. MiR-181c [27] and MiR-96 [28] can ameliorate cognitive dysfunction by regulating autophagy in CCH [29]. In general, demyelination, inflammatory responses, and mitochondrial dysfunction are common pathways leading to cognitive dysfunction [30,31], which can ameliorate the prognosis of chronic cortical hypoperfusion by reducing white matter lesions.…”

Exploring the Roles of CREBRF and TRIM2 in the Regulation of Angiogenesis by High-Density Lipoproteins

“…One example is the finding that TRIM2 is a target of non-coding microRNA-181c [ 34 ], which has been implicated in cancer signalling [ 35 , 36 , 37 ]. A recent in vivo study also demonstrated that microRNA-181c, through its modulation of TRIM2 , can attenuate cognitive impairment in rats induced by chronic cerebral ischemia [ 38 ]. In the case of CREBRF , the rapid turnover of CREBRF protein, with a reported half-life of less than 20 min [ 24 ], may also account for the lack of changes seen at the protein level.…”

Brain Energy and Oxygen Metabolism: Emerging Role in Normal Function and Disease

“…In a model of chronic cerebral hypoperfusion miR-181c was continuously inhibited, correlating with upregulation of its plasticity-related target gene, TRIM2. Hypoperfusion in this model was associated with deficits in spatial learning that were ameliorated by hippocampal overexpression of miR-181c (Fang et al, 2017 ). These studies all provide support to the hypothesis that metabolically regulated genes are directly involved in the regulation of neuronal plasticity.…”