Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia

Hao Han; Yawei Zhao; Junda Du; Sushan Wang; Xuehan Yang; Weijie Li; Jiayi Song; Siwei Zhang; Ziyi Zhang; Yongfei Tan; Grant M Hatch; Ming Zhang; Li Chen

doi:10.1186/s12979-023-00390-4

Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia

Immun Ageing. 2023 Nov 17;20(1):63. doi: 10.1186/s12979-023-00390-4.

Authors

Hao Han^#^{1

2}, Yawei Zhao^#^{1

2}, Junda Du³, Sushan Wang^{1

2}, Xuehan Yang^{1

2}, Weijie Li^{1

2}, Jiayi Song^{1

2}, Siwei Zhang^{1

2}, Ziyi Zhang⁴, Yongfei Tan⁵, Grant M Hatch⁶, Ming Zhang^{7

8}, Li Chen^{9

10}

Affiliations

¹ Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
² Department of Pharmacology, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, 130021, Jilin, China.
³ School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China.
⁴ The Second Hospital of Jilin University, Changchun, 130041, China.
⁵ South China Institute of Collaborative Innovation, Dongguan, 523808, China.
⁶ Departments of Pharmacology and Therapeutics, Biochemistry and Medical Genetics, Center for Research and Treatment of Atherosclerosis, DREAM Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, R3E0T6, Canada.
⁷ Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China. zhangming99@jlu.edu.cn.
⁸ Department of Pharmacology, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, 130021, Jilin, China. zhangming99@jlu.edu.cn.
⁹ Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China. chenl@jlu.edu.cn.
¹⁰ Department of Pharmacology, College of Basic Medical Sciences, Jilin University, 126 Xin Min Street, Changchun, 130021, Jilin, China. chenl@jlu.edu.cn.

^# Contributed equally.

Abstract

Background: Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory.

Results: Microglia were hyperactivated in the brains of AlCl₃/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype.

Conclusion: The elevated lactate acted as an "accelerator" of the endogenous "lactate timer" in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.

Keywords: Alzheimers disease; Exercise; Lactate; Lactylation; Microglia; Neuroinflammation.