Physical Exercise Ameliorates the Cognitive Function and Attenuates the Neuroinflammation of Alzheimer’s Disease via miR-129–5p

Abstract

Introduction: Physical exercise has a significant neuroprotective role in Alzheimer's disease (AD), but the underlying mechanisms remain elusive. Objective: This study aimed to explore the molecular mechanisms of physical exercise by analyzing the role of microRNA-129-5p (miR-129-5p) in AD mice and patients. Methods: AD mice and patients were treated with 4-week and 3-month physical exercise, respectively. The expression of miR-129-5p was measured using quantitative realtime PCR. The Morris water-maze test was used for cognition evaluation, and enzyme-linked immunosorbent assay was used for inflammation analysis. Results: In both AD mice and patients, the expression of miR-129-5p was elevated by physical exercise. By in vivo regulation of miR-129-5p, we found that the improved cognitive function and reduced inflammatory responses were reversed by the knockdown of miR-129-5p. In patients with AD, the serum expression of miR-129-5p was further found to be correlated with the serum levels of cognitive function markers and proinflammatory cytokines. Conclusion: All data indicated that the expression of miR-129-5p in AD mice and patients is significantly upregulated by physical exercise. The knockdown of miR-129-5p can abrogate the neuroprotective effect of exercise on cognition and neuroinflammation in AD mice. This study provides a novel insight into the molecular mechanisms underlying the neuroprotective effect of physical exercise in AD, and miR-129-5p may provide a novel therapeutic target for AD treatment.

A method for simultaneous detection of small and long RNA biotypes by ribodepleted RNA-Seq

“…Similarly in human post-mortem AD samples, we identified key differentially-expressed genes such as GFAP (log2 FC 1.48, p < 0.0001), SERPING1 (log2 FC 1.02, p < 0.05), KRT5 (log2 FC -3.52, p < 0.0001), and NEUROD6 (log2 FC -1.23, p < 0.05), all genes that have been reported to be altered in AD 38 (Supplementary Table S2 ). We also identified differentially-expressed miRNA that had previously been discovered in APP/PS1 mice 39 , 40 (miR-26a-5p, log2 FC 0.58, p < 0.05; miR-7b-5p, log2 FC -0.55, p < 0.05; Supplementary Table S3 ) and human AD patients 41 , 42 (miR-129-5p, log2 FC -1.14, p < 0.05; miR-151b, log2 FC -1.28, p < 0.05; Supplementary Table S4 ). As is often recommended for RNA-Seq experiments, further investigation and validation of differentially-expressed transcripts by, for example, quantitative RT-PCR would address concerns with regards to quantification.…”

LncRNA HOTAIR in exercise-induced neuro-protective function in Alzheimer’s disease

“…For example, the exercise meliorates MMSE and ADAS-Cog scores, and inhibits the raised expression of lncRNA SNHG14 [13]. In another investigation of AD patients, the levels of miR-129-5p were enhanced induced by physical exercise, and correlations were identified between miR-129-5p and ADAS-Cog and MMSE scores [17]. Therefore, we further analyzed the association between HOTAIR and cognition.…”

Mechanisms Underlying Non-Pharmacological Dementia Prevention Strategies: A Translational Perspective

“…Some studies have shown that plaque-associated astrocytes decrease in number or complexity (20,63), while others observe them as being more active around the plaques (13). The ameliorated neuroinflammation may be attributed to activation of the miR-129-5p (16) or inhibition of the JNK pathway and its down-stream targets (11,44). Since JNK pathway is a down-stream target of receptor p75 (38), JNK pathway mediated reduction in neuroinflammation could be linked to changes in BDNF levels.…”

“…Extensive studies performed on dementia mouse models exposed to exercise training report positive outcomes in cognitive tests (10)(11)(12)(13)(14)(15)(16)(17)(18). Many of these studies report an increase of synaptic markers indicating preservation of synapses and their function in the brains of exercising mice (10)(11)(12)(13)(14)19).…”

“…In APP/PS1 mice, exercise reduced the count and intensity of plaque-associated astrocytes (20) while in physically active 5xFAD mice they were increased (13). The reduced neuroinflammation is suggested to be mediated via inhibition of the c-Jun N-terminal kinase (JNK) pathway (11) or activation of the microRNA miR-129-5p (16).…”