Exercise improves choroid plexus epithelial cells metabolism to prevent glial cell-associated neurodegeneration

Yisheng Chen; Zhiwen Luo; Yaying Sun; Fangqi Li; Zhihua Han; Beijie Qi; Jinrong Lin; Wei-Wei Lin; Mengxuan Yao; Xueran Kang; Jiebin Huang; Chenyu Sun; Chenting Ying; Chenyang Guo; Yuzhen Xu; Jiwu Chen; Shiyi Chen

doi:10.3389/fphar.2022.1010785

Exercise improves choroid plexus epithelial cells metabolism to prevent glial cell-associated neurodegeneration

Front Pharmacol. 2022 Sep 16:13:1010785. doi: 10.3389/fphar.2022.1010785. eCollection 2022.

Authors

Yisheng Chen¹, Zhiwen Luo¹, Yaying Sun¹, Fangqi Li¹, Zhihua Han², Beijie Qi¹, Jinrong Lin¹, Wei-Wei Lin³, Mengxuan Yao⁴, Xueran Kang⁵, Jiebin Huang⁶, Chenyu Sun⁷, Chenting Ying⁸, Chenyang Guo², Yuzhen Xu⁹, Jiwu Chen², Shiyi Chen¹

Affiliations

¹ Huashan Hospital, Fudan University, Shanghai, China.
² Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
⁴ Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei.
⁵ Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, Hebei.
⁶ Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ AMITA Health Saint Joseph Hospital Chicago, Chicago, IL, United States.
⁸ Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁹ Department of Rehabilitation, The Second Affiliated Hospital of Shandong First Medical University, Taian, China.

Abstract

Recent studies have shown that physical activities can prevent aging-related neurodegeneration. Exercise improves the metabolic landscape of the body. However, the role of these differential metabolites in preventing neurovascular unit degeneration (NVU) is still unclear. Here, we performed single-cell analysis of brain tissue from young and old mice. Normalized mutual information (NMI) was used to measure heterogeneity between each pair of cells using the non-negative Matrix Factorization (NMF) method. Astrocytes and choroid plexus epithelial cells (CPC), two types of CNS glial cells, differed significantly in heterogeneity depending on their aging status and intercellular interactions. The MetaboAnalyst 5.0 database and the scMetabolism package were used to analyze and calculate the differential metabolic pathways associated with aging in the CPC. These mRNAs and corresponding proteins were involved in the metabolites (R)-3-Hydroxybutyric acid, 2-Hydroxyglutarate, 2-Ketobutyric acid, 3-Hydroxyanthranilic acid, Fumaric acid, L-Leucine, and Oxidized glutathione pathways in CPC. Our results showed that CPC age heterogeneity-associated proteins (ECHS1, GSTT1, HSD17B10, LDHA, and LDHB) might be directly targeted by the metabolite of oxidized glutathione (GSSG). Further molecular dynamics and free-energy simulations confirmed the insight into GSSG's targeting function and free-energy barrier on these CPC age heterogeneity-associated proteins. By inhibiting these proteins in CPC, GSSG inhibits brain energy metabolism, whereas exercise improves the metabolic pathway activity of CPC in NVU by regulating GSSG homeostasis. In order to develop drugs targeting neurodegenerative diseases, further studies are needed to understand how physical exercise enhances NVU function and metabolism by modulating CPC-glial cell interactions.

Keywords: Alzheimer’s disease; astrocytes; brain energy metabolism; choroid plexus epithelial cells; exercise; multicomics; pharmacology.