Exercise training upregulates Dicer to modulate hippocampal miRNA expression in 5xFAD mice

Abstract

Changes to cerebral miRNA expression have been implicated in the progression of Alzheimer’s disease (AD), as miRNAs that regulate the expression of genes involved in amyloid beta (Aβ) processing are dysregulated in those that suffer from AD. Exercise training improves cognitive function and reduces Aβ plaque burden, however, the mechanisms are not fully understood. Using our progressive weighted wheel running (PoWeR) exercise program, which utilizes an unbalanced running wheel to promote physiological adaptations similar to those seen in humans, we assessed the effect of 20 weeks of voluntary exercise training on changes in cognitive function and hippocampal miRNA expression in female 5xFAD mice; a model that expresses human APP and PSEN1 transgenes with a total of five AD‐linked mutations. Two month old female 5xFAD mice were PoWeR trained for 20 weeks, running ~7km/day, while groups of female wild‐type (B6SJLF1/J) and 5xFAD served as sedentary controls. At the end of the training period, mice performed cognitive (Morris water maze, novel object recognition) and physical (rotor rod and balance beam) function tests. The hippocampus was removed to assess miRNA abundance via Nanostring and gene expression with RT‐qPCR. Exercise training improved cognitive and physical function, in addition to having a significant effect on the expression of the miRNA processing enzyme, Dicer. Specifically, Dicer was lower in sedentary 5xFAD hippocampus, when compared to sedentary WT mice, but was robustly elevated following exercise. Correspondingly, ~45% of the miRNAs that were dysregulated in sedentary 5xFAD mice were restored towards wild‐type levels following exercise. Specifically, miR‐29, which is a validated target of the APP processing protein, BACE1, was significantly higher in exercised 5xFAD mice. Accordingly, BACE1 expression was lower in these mice. Based on these results, we conclude that exercise training alters cerebral miRNA expression via Dicer to affect APP processing.Support or Funding InformationNIH AG049806 to J.J.M and C.A.P.NIH P30 AG028383 to C.M.D.