MicroRNA modulation is a potential molecular mechanism for neuroprotective effects of intranasal insulin administration in amyloid βeta oligomer induced Alzheimer's like rat model.

Abstract

Substantial evidence indicates that imbalance in the expression of miR-132-3p, miR-181b-5p, miR-125b-5p, miR-26a-5p, miR-124-3p, miR-146a-5p, miR-29a-3p, and miR-30a-5p in the AD brain are associated with amyloid-beta (Aβ) aggregation, tau pathology, neuroinflammation, and synaptic dysfunction, the major pathological hallmarks of Alzheimer's disease)AD(. Several studies have reported that intranasal insulin administration ameliorates memory in AD patients and animal models. However, the underlying molecular mechanisms are not yet completely elucidated. Therefore, the aim of this study was to determine whether insulin is involved in regulating the expression of AD-related microRNAs. Pursuing this objective, we first investigated the therapeutic effect of intranasal insulin on Aβ oligomer (AβO)-induced memory impairment in male rats using the Morris water maze task. Then, molecular and histological changes in response to AβO and/or insulin time course were assessed in the extracted hippocampi on days 1, 14, and 21 of the study using congo red staining, western blot and quantitative real-time PCR analyses. We observed memory impairment, Aβ aggregation, tau hyper-phosphorylation, neuroinflammation, insulin signaling dys-regulation, and down-regulation of miR-26a, miR-124, miR-29a, miR-181b, miR-125b, miR-132, and miR-146a in the hippocampus of AβO-exposed rats 21days after AβO injection. Intranasal insulin treatment ameliorated memory impairment and concomitantly increased miR-132, miR-181b, and miR-125b expression, attenuated tau phosphorylation levels, Aβ aggregation, and neuroinflammation, and regulated the insulin signaling as well. In conclusion, our study suggest that the neuroprotective effects of insulin on memory observed in AD-like rats could be partially due to the restoration of miR-132, miR-181b, and miR-125b expression in the brain.