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

(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.