MicroRNA-140-5p inhibitor attenuates memory impairment induced by amyloid-ß oligomer in vivo possibly through Pin1 regulation.

Abstract

The peptidyl-prolyl cis/trans isomerase, Pin1, has a protective role in age-related neurodegeneration by targeting different phosphorylation sites of tau and the key proteins required to produce Amyloid-β, which are the well-known molecular signatures of Alzheimer's disease (AD) neuropathology. The direct interaction of miR-140-5p with Pin1 mRNA and its inhibitory role in protein translation has been identified. The main purpose of this study was to investigate the role of miRNA-140-5p inhibition in promoting Pin1 expression and the therapeutic potential of the AntimiR-140-5p in the Aß oligomer (AßO)-induced AD rat model. Spatial learning and memory were assessed in the Morris water maze. RT-PCR, western blot, and histological assays were performed on hippocampal samples at various time points after treatments. miRNA-140-5p inhibition enhanced Pin1 and ADAM10 mRNA expressions but has little effect on Pin1 protein level. The miRNA-140-5p inhibitor markedly ameliorated spatial learning and memory deficits induced by AßO, and concomitantly suppressed the mRNA expression of inflammatory mediators TNFα and IL-1β, and phosphorylation of tau at three key sites (thr231, ser396, and ser404) as well as increased phosphorylated Ser473-Akt. According to our results, Antimir-140-mediated improvement of AβO-induced neuronal injury and memory impairment in rats may provide an appropriate rationale for evaluating miR-140-5p inhibitors as a promising agent for the treatment of AD.