microRNA-195 Alleviates Cognitive Impairment in Rat following Chronic Brain Hypoperfusion

Objective To observe whether chronic brain hypoperfusion (CBH) induced cognitive decline is associated with amyloid‐β (Aβ)‐cascade response process, dendritic degeneration and neuron death in the hippocampus as well as septal‐hippocampal cholinergic circuit disorder. Methods and results We found that bilateral common carotid artery occlusion (2VO) generated CBH could induce significant cognitive decline and decreased fEPSP of septal‐hippocampal cholinergic circuit in rats, assessed by Morris water maze and in vivo electrophysiological recording. Subsequently, we found the overexpressed protein levels of amyloid precursor protein (APP) and β‐site APP cleaving enzyme 1 (BACE1), death receptor 6 (DR6), together with an activated cdk5/p25, glycogen synthase kinase 3β (GSK3β), inactivated protein phosphatase 2A, degenerated dendrites and neuron death in the hippocampus, as evaluated by western blotting, Golgi, TUNEL and immunofluorescence staining. Interestingly, microRNA‐195 ( miR‐195 ) was found decreased in both hippocampus and basal forebrain. By bioinformatic prediction , we found that miR‐195 could target on 3’‐untranslated regions of Aβ cascade response related genes, including APP , BACE1 , Cdk5r1 , PME‐1 and Death receptor 6 . Further study revealed that miR‐ 195 regulated the expression of APP, BACE1, p35, methylesterase (PME‐1) and DR6 protein at the post‐transcriptional level, as assessed by Dual luciferase reporter assay, siRNA and miR‐masking techniques. In vivo , knockdown of endogenous miR‐195 by lentiviral vector‐mediated over‐expression of its antisense molecule (lenti‐pre‐AMO‐195) elicited the phenotype of dementia and upregulated protein levels of APP, BACE1, p35, PME‐1 and DR6 in rats, whereas over‐expression of miR‐195 using lenti‐pre‐miR‐195 reduced dementia‐vulnerability and those protein levels triggered by CBH. Additionally, chromatin immunoprecipitation analysis showed that NFκB was bound to the promoter region of miR‐195 and inhibited its expression. Conclusion CBH could induce cognitive impairment involving Aβ aggregation, hyperphosphorylation of Tau, GSK3β activation, protein phosphatase‐2A inactivation, degeneration of dendrites and neuron death, which is associated with chronic brain hypoxia‐activated NFκB that inhibited endogenous biogenesis of miR‐195 . Down‐regulation of miR‐195 up‐regulated the expression of a battery of Aβ cascade response related proteins at the post‐transcriptional level. MiR‐195 may play a key role in determining dementia susceptibility in CBH rats through a multi‐target way at the post‐transcriptional level, and exogenous complement of miR‐195 may be a potentially valuable anti‐dementia approach. Support or Funding Information Foundation: This work was supported by Natural Science Foundation of China (81271207, 81070882, 81000499, 81471115, 81671052 and 81371211). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .