ADAM10 suppresses demyelination and reduces seizure susceptibility in cuprizone-induced demyelination model

Xinjian Zhu; Yuanyuan Yao; Jiurong Yang; Canyu Zhang; Xinyan Li; Aifeng Zhang; Xiufang Liu; Chenchen Zhang; Guangming Gan

doi:10.1016/j.freeradbiomed.2021.05.001

ADAM10 suppresses demyelination and reduces seizure susceptibility in cuprizone-induced demyelination model

Free Radic Biol Med. 2021 Aug 1:171:26-41. doi: 10.1016/j.freeradbiomed.2021.05.001. Epub 2021 May 6.

Authors

Xinjian Zhu¹, Yuanyuan Yao², Jiurong Yang², Canyu Zhang², Xinyan Li², Aifeng Zhang³, Xiufang Liu⁴, Chenchen Zhang⁵, Guangming Gan⁶

Affiliations

¹ Department of Pharmacology, Medical School of Southeast University, Nanjing, China. Electronic address: xinjianzhu@seu.edu.cn.
² Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
³ Department of Pathology, Medical School of Southeast University, Nanjing, China.
⁴ Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing, China.
⁵ Transmission Electron Microscopy Center, Medical School of Southeast University, Nanjing, China.
⁶ Transmission Electron Microscopy Center, Medical School of Southeast University, Nanjing, China; Department of Genetics and Developmental Biology, Medical School of Southeast University, Nanjing, China.

PMID: 33965566
DOI: 10.1016/j.freeradbiomed.2021.05.001

Abstract

The metalloproteinase ADAM10 is the most important amyloid precursor protein (APP) α-secretase, preventing the deposit of neurotoxic amyloid β (Aβ) peptide and generating a soluble APP fragment (sAPP_α) with neurotrophic functions. Recent studies have suggested that ADAM10 also play a role in the pathogenesis of inflammatory CNS diseases, such as multiple sclerosis (MS). Demyelination is the hallmarks of MS but the mechanisms involved remain unclear. Here in this study, we examined the role that ADAM10 might play in the cuprizone-induced demyelination model. Our results demonstrated that ADAM10 expression and sAPP_α production were significantly reduced in the corpus callosum in response to cuprizone treatment. Overexpression of ADAM10 increased sAPP_α production and suppressed demyelination as well as neuroinflammation and oxidative stress in cuprizone-induced demyelination model. Pharmacological inhibition of ADAM10 activity, however, abrogates the protective effect of ADAM10 against demyelination, neuroinflammation and oxidative stress. It has been reported that CNS demyelination may induce seizure activity. Here, we found that overexpression of ADAM10 reduced seizure susceptibility in cuprizone-induced demyelination model, suggesting that ADAM10-derived sAPP_α suppresses demyelination and reduces seizure susceptibility via ameliorating neuroinflammation and oxidative stress in cuprizone-induced demyelination model.

Keywords: ADAM10; Demyelination; Neuroinflammation; Oxidative stress; Seizure susceptibility; sAPP(α).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM10 Protein / genetics
Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides
Animals
Corpus Callosum / metabolism
Cuprizone* / toxicity
Demyelinating Diseases* / chemically induced
Demyelinating Diseases* / genetics
Disease Models, Animal
Membrane Proteins / genetics
Mice
Mice, Inbred C57BL
Seizures / chemically induced
Seizures / drug therapy
Seizures / genetics

Substances

Amyloid beta-Peptides
Membrane Proteins
Cuprizone
Amyloid Precursor Protein Secretases
ADAM10 Protein
Adam10 protein, mouse