Exercise-mediated alteration of hippocampal Dicer mRNA and miRNAs is associated with lower BACE1 gene expression and Aβ1-42 in female 3xTg-AD mice

Dungan CM, Valentino T, Vechetti IJ Jr, Zdunek CJ, Murphy MP, Lin AL, McCarthy JJ, Peterson CA. Exercise-mediated alteration of hippocampal Dicer mRNA and miRNAs is associated with lower BACE1 gene expression and Al31-42 in female 3xTg-AD mice. J Neurophysiol 124: 1571-1577, 2020. First published October 14, 2020; doi:10.1152/jn.00503.2020.-Changes to cerebral miRNA expression have been implicated in the progression of Alzheimer's disease (AD), as miRNAs that regulate the expression of gene products involved in amyloid beta (Al3) processing, such as BACE1, are dysregulated in those that suffer from AD. Exercise training improves cognition and reduces BACE1 and Al3-plaque burden; however, the mechanisms are not fully understood. Using our progressive weighted wheel running (PoWeR) exercise program, we assessed the effect of 20 wk of exercise training on changes in hippocampal miRNA expression in female 3xTg-AD (3xTg) mice. PoWeR was sufficient to promote muscle hypertrophy and increase myonuclear abundance. Furthermore, PoWeR elevated hippocampal Dicer gene expression in 3xTg mice, while altering miRNA expression toward a more wild-type profile. Specifically, miR-29, which is validated to target BACE1, was significantly lower in sedentary 3xTg mice when compared with wild-type but was elevated following PoWeR. Accordingly, BACE1 gene expression, along with detergent-soluble Al31-42, was lower in PoWeR-trained 3xTg mice. Our data suggest that PoWeR training upregulates Dicer gene expression to alter cerebral miRNA expression, which may contribute to reduced Al3 accumulation and delay AD progression. NEW & NOTEWORTHY Previous studies have outlined the beneficial effects of exercise on lowering BACE1 expression and reducing Al3 plaques. This study extends upon the work of others by outlining a new potential mechanism by which exercise elicits beneficial effects on Alzheimer's disease pathology, specifically through modulation of Dicer and miRNA expression. This is the first study to examine Dicer and miRNA expression in the hippo campus of the 3xTg model within the context of exercise.