Moderate-Intensity Intermittent Training Alters the DNA Methylation Pattern of PDE4D Gene in Hippocampus to Improve the Ability of Spatial Learning and Memory in Aging Rats Reduced by D-Galactose

Abstract

(1) Background: Aging is the main risk factor for most neurodegenerative diseases, and the inhibition of Phosphodiesterase 4(PDE4) is considered a potential target for the treatment of neurological diseases. The purpose of this study was to investigate the inhibitory effect of moderate-intensity intermittent training (MIIT) on PDE4 in the hippocampus of rats with D-galactose (D-gal)-induced cognitive impairment, and the possible mechanism of improving spatial learning and memory. (2) Methods: the aging rats were treated with D-Gal (150 mg/kg/day, for 6 weeks). The aging rats were treated with MIIT for exercise intervention (45 min/day, 5 days/week, for 8 weeks). The Morris water maze test was performed before and after MIIT to evaluate the spatial learning and memory ability, then to observe the synaptic ultrastructure of the hippocampus CA1 region, to detect the expression of synaptic-related protein synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), and to detect the expression of PDE4 subtypes, cAMP, and its signal pathway protein kinase A (PKA)/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF), and the PDE4 methylation level. (3) Results: we found that MIIT for 8 weeks alleviated the decline in spatial learning and memory ability, and improved the synaptic structure of the hippocampus and the expression of synaptic protein SYP and PSD95 in D-Gal aging rats. To elucidate the mechanism of MIIT, we analyzed the expression of PDE4 isoforms PDE4A/PDE4B/PDE4D, cAMP, and the signaling pathway PKA/CREB/BDNF, which play an important role in memory consolidation and maintenance. The results showed that 8 weeks of MIIT significantly up-regulated cAMP, PKA, p-CREB, and BDNF protein expression, and down-regulated PDE4D mRNA and protein expression. Methylation analysis of the PDE4D gene showed that several CG sites in the promoter and exon1 regions were significantly up-regulated. (4) Conclusions: MIIT can improve the synaptic structure of the hippocampus CA1 area and improve the spatial learning and memory ability of aging rats, which may be related to the specific regulation of the PDE4D gene methylation level and inhibition of PDE4D expression.

Effects of exercise-targeted hippocampal PDE-4 methylation on synaptic plasticity and spatial learning/memory impairments in D-galactose-induced aging rats

“…Moreover, since a previous study has shown the role of PDE4 in hippocampal neurogenesis (Li et al 2009 ), we believe that exercise-driven PDE4 methylation will improve learning functions via facilitating both neurogenesis and synaptogenesis. The current results support our findings suggesting a critical role for exercise training in promoting cognitive function by increasing PDE-4 methylation (Zhang et al 2023 ). The current data further broaden our understandings for central effects of exercise, which leads to the neural recovery covering neuronal oxidative stress and synaptic plasticity.…”

Bioinformatics Analysis and Experimental Verification of Exercise for Aging Mice in Different Brain Regions Based on Transcriptome Sequencing

“…In an aging rat model induced by D-galactose, 6-8 weeks of moderate-intensity exercise training improved spatial learning and memory [15,17]. Voluntary exercise mitigated cognitive deficits and suppressed neural degeneration in the hippocampus of senescenceaccelerated SAMP8 mice [18].…”

Time-resolved map of serum metabolome profiling in D-galactose-induced aging rats with exercise intervention

“… 70 After the injection of D-gal, the rats from AE groups were submitted to aerobic intermittent training on a treadmill (Shanghai Xinruan Information Technology Co., Ltd., Shanghai, China) for 5 days per week and continued for 8 weeks. 71 Firstly, the rats performed warm-up exercises for 10 min (intensity: 50%-60% of maximal oxygen uptake (VO 2 max), 10 m/min) on a treadmill under 0° slope condition. Secondly, rats ran for 4 min (intensity: 80%-90% of VO 2 max, 20 m/min) under the same condition.…”