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

Jinmei Zhang; Qiaojing Gao; Jun Gao; Liting Lv; Renfan Liu; Yi Wu; Xue Li; Yu Jin; Lu Wang

doi:10.3390/brainsci13030422

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

Brain Sci. 2023 Feb 28;13(3):422. doi: 10.3390/brainsci13030422.

Authors

Jinmei Zhang^{1

2}, Qiaojing Gao¹, Jun Gao¹, Liting Lv¹, Renfan Liu¹, Yi Wu¹, Xue Li¹, Yu Jin¹, Lu Wang¹

Affiliations

¹ School of Sports Medicine and Health, Chengdu Sport University, Chengdu 610041, China.
² School of Physical Education, Chaohu University, Hefei 238000, China.

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.

Keywords: PDE4; aging; hippocampus; learning and memory; moderate-intensity intermittent training.

Grants and funding

The study is funded by seven research projects. The details are as follows: National Natural Science Foundation of China (grant number:31900848); the Project Foundation of Sichuan Provincial Department of Science and Technology (grant number:2022NSFSC1724); the Sichuan Key Laboratory of Sports Medicine and or the Key Laboratory of Sports Medicine of the State Administration of Sports (grant number:2022-A045); the Innovative Project of Chengdu Institute of Physical Education and Health Institute/Zheng Huaixian Bone and Trauma Research Institute from 2021 to 2022 (grant nos:CX21B05, CX21C09, CX21A02); the Scientific Research Project of Anhui Province Department of Education (grant number:2022AH051691).