Exosomal MicroRNAs modulate the cognitive function in fasudil treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice model of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is characterized by cognitive impairment caused by the accumulation of beta-amyloid (Aβ) plaques and trans-synaptic spread of tau pathology. Exosome has emerged as key mediators for neuronal development, maintenance, and cellular communication. However, the molecular mechanism of exosomal miRNAs related to AD remains unknown. In the present study, APPswe/PSEN1dE9 transgenic (APP/PS1) mice (AD) were treated with vehicle (ADNS) and fasudil (ADF), whereas C57BL/6 (control) mice were treated with vehicle (WT). Cognitive function was assessed by Y-maze test and AD pathology was confirmed by immunostaining of Aβ plaque and phosphorylated tau. Exosomal RNAs from each mouse of the group were extracted, sequenced and analyzed. Our results showed amelioration of cognitive function, decreased Aβ plaque load, and phosphorylated tau protein after fasudil treatment. Exosomal miRNA analysis showed 3 miRNAs (mmu-let-7i-5p, mmu-miR-19a-3p, mmu-miR-451a) in the intersection of ADNS vs ADF and WT vs ADNS. GO annotation and KEGG pathway showed the target gene of miR-19a-3p are Pten and Tnf; mmu-miR-451a are Nsmaf, Gnai3 and Akt3. In conclusions, fasudil treatment improved cognitive function by regulating exosomal MicroRNAs (mmu-miR-451a and mmu-miR-19a-3p). These MicroRNAs could be potential biomarker of AD and therapeutic target for novel treatment for AD.