Effects of Exercise-targeted Hippocampal PDE-4 Methylation on Synaptic Plasticity and Spatial Learning/memory Impairments in D-galactose-induced Aging Rats

Overview

Journal Exp Brain Res

Specialty Neurology

Date 2023 Dec 5

PMID 38052997

Authors

Yu Jin

Xue Li

Changling Wei

Qiongjia Yuan

Affiliations

Soon will be listed here.

Abstract

Physical exercise reduces the effects of aging and cognitive decline by improving synaptic plasticity and spatial learning. However, the underlying neurobiological mechanisms are unclear. A total of 45 Male SPF Sprague-Dawley rats were acclimatized and then allocated into three groups, 15 in each group: the saline control (DC) group, D-gal-induced aging (DA) group, and D-gal-induced aging + exercise (DE) group. Six weeks of intraperitoneal injections of D-gal at a concentration of 100 mg/kg body weight/d was injected to establish model of aging in the DA and DE groups. Morris water maze test was implemented to evaluate the hippocampus related cognition. SOD activity and MDA was tested to assess the aging in all groups. H&E and Nissl staining was used to observe the histopathological changes of hippocampal neurons in aging rats. Quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining techniques were used to investigate the expression of synaptic genes and proteins in the hippocampus. Massarray methylation system was employed to measure the PDE-4 gene methylation level in rat hippocampal tissues. Our results demonstrated that exercise intervention improves cognitive function in D-gal-induced aging rats. The methylation of CpG sites in PDE-4 in the hippocampus was significantly increased. The physical exercise significantly increased PDE-4 gene methylation and effectively decreased PDE-4 gene and protein expression. These beneficial behavioral and morphological effects were attributed to PDE-4 methylation, which was activated cAMP/PKA/CREB pathway and improved synaptic plasticity. Exercise induced PDE-4 methylation is key mechanism underpinning the amelioration of learning/memory impairment, suggesting the potential efficacy of physical exercise training in delaying brain aging.

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References

Li X, Wang L, Zhang S, Hu X, Yang H, Xi L . Timing-Dependent Protection of Swimming Exercise against d-Galactose-Induced Aging-Like Impairments in Spatial Learning/Memory in Rats. Brain Sci. 2019; 9(9). PMC: 6770394. DOI: 10.3390/brainsci9090236. View

Li Y, Huang Y, Amsdell S, Xiao L, ODonnell J, Zhang H . Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus. Neuropsychopharmacology. 2009; 34(11):2404-19. PMC: 2743762. DOI: 10.1038/npp.2009.66. View

Epp J, Spritzer M, Galea L . Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation. Neuroscience. 2007; 149(2):273-85. DOI: 10.1016/j.neuroscience.2007.07.046. View

Heckman P, Blokland A, Bollen E, Prickaerts J . Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations. Neurosci Biobehav Rev. 2018; 87:233-254. DOI: 10.1016/j.neubiorev.2018.02.007. View

Kandel E . The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain. 2012; 5:14. PMC: 3514210. DOI: 10.1186/1756-6606-5-14. View

Villeda S, Plambeck K, Middeldorp J, Castellano J, Mosher K, Luo J . Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014; 20(6):659-63. PMC: 4224436. DOI: 10.1038/nm.3569. View

Partridge L, Deelen J, Slagboom P . Facing up to the global challenges of ageing. Nature. 2018; 561(7721):45-56. DOI: 10.1038/s41586-018-0457-8. View

Blokland A, Heckman P, Vanmierlo T, Schreiber R, Paes D, Prickaerts J . Phosphodiesterase Type 4 Inhibition in CNS Diseases. Trends Pharmacol Sci. 2019; 40(12):971-985. DOI: 10.1016/j.tips.2019.10.006. View

Dias-Santagata D, Fulga T, Duttaroy A, Feany M . Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest. 2006; 117(1):236-45. PMC: 1697799. DOI: 10.1172/JCI28769. View

10.

Schreiber R, Hollands R, Blokland A . A Mechanistic Rationale for PDE-4 Inhibitors to Treat Residual Cognitive Deficits in Acquired Brain Injury. Curr Neuropharmacol. 2019; 18(3):188-201. PMC: 7327948. DOI: 10.2174/1570159X17666191010103044. View

11.

Manabe T, Racz I, Schwartz S, Oberle L, Santarelli F, Emmrich J . Systemic inflammation induced the delayed reduction of excitatory synapses in the CA3 during ageing. J Neurochem. 2021; 159(3):525-542. DOI: 10.1111/jnc.15491. View

12.

Lombroso P, Ogren M . Learning and memory, part I: brain regions involved in two types of learning and memory. J Am Acad Child Adolesc Psychiatry. 2008; 47(11):1228-32. DOI: 10.1097/CHI.0b013e318186e638. View

13.

Peng H, Hu B, Xie L, Su T, Li C, Liu Y . A mechanosensitive lipolytic factor in the bone marrow promotes osteogenesis and lymphopoiesis. Cell Metab. 2022; 34(8):1168-1182.e6. DOI: 10.1016/j.cmet.2022.05.009. View

14.

Zhang J, Gao Q, Gao J, Lv L, Liu R, Wu Y . 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; 13(3). PMC: 10046546. DOI: 10.3390/brainsci13030422. View

15.

Chen X, Ganetzky B . A neuropeptide signaling pathway regulates synaptic growth in Drosophila. J Cell Biol. 2012; 196(4):529-43. PMC: 3283997. DOI: 10.1083/jcb.201109044. View

16.

Kader F, Ghai M, Maharaj L . The effects of DNA methylation on human psychology. Behav Brain Res. 2017; 346:47-65. DOI: 10.1016/j.bbr.2017.12.004. View

17.

Song S, Lam E, Tchkonia T, Kirkland J, Sun Y . Senescent Cells: Emerging Targets for Human Aging and Age-Related Diseases. Trends Biochem Sci. 2020; 45(7):578-592. PMC: 7649645. DOI: 10.1016/j.tibs.2020.03.008. View

18.

Chiricozzi A, Caposiena D, Garofalo V, Cannizzaro M, Chimenti S, Saraceno R . A new therapeutic for the treatment of moderate-to-severe plaque psoriasis: apremilast. Expert Rev Clin Immunol. 2015; 12(3):237-49. DOI: 10.1586/1744666X.2016.1134319. View

19.

Xiao J, Yao R, Xu B, Wen H, Zhong J, Li D . Inhibition of PDE4 Attenuates TNF-α-Triggered Cell Death Through Suppressing NF-κB and JNK Activation in HT-22 Neuronal Cells. Cell Mol Neurobiol. 2019; 40(3):421-435. PMC: 11448866. DOI: 10.1007/s10571-019-00745-w. View

20.

Chen D, Zhang Y, Zhang M, Chang J, Zeng Z, Kou X . Exercise Attenuates Brain Aging by Rescuing Down-Regulated Wnt/β-Catenin Signaling in Aged Rats. Front Aging Neurosci. 2020; 12:105. PMC: 7192222. DOI: 10.3389/fnagi.2020.00105. View