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Research Paper|Volume 12, Issue 14|pp 14232—14243

Minocycline inhibition of microglial rescues nigrostriatal dopaminergic neurodegeneration caused by mutant alpha-synuclein overexpression

Yong Wang1, Qian Wang2,3, Ruobing Yu4, Qi Zhang5, Zhonghai Zhang6, Haiying Li7, Chao Ren8, Rongli Yang2,3, Haichen Niu4,9
  • 1Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
  • 2Affiliated First Clinical College of Xuzhou Medical University, Xuzhou 221004, China
  • 3Department of Geriatric Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221004, China
  • 4Department of Genetics, Xuzhou Medical University, Xuzhou 221004, China
  • 5Experimental Animal Center, Xuzhou Medical University, Xuzhou 221004, China
  • 6Deprtment of Physiology, Xuzhou Medical University, Xuzhou 221004, China
  • 7Department of Pathology, Xuzhou Medical University, Xuzhou 221004, China
  • 8Department of Neurology, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, China
  • 9Public Experimental Research Center of Xuzhou Medical University, Xuzhou 221004, China
* Equal contribution and co-first authors
Received: February 7, 2020Accepted: May 25, 2020Published: July 24, 2020
https://doi.org/10.18632/aging.103440

Copyright: © 2020 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Studies indicate that mutant α-synuclein (mαSyn) is involved in the pathogenesis of Parkinson’s disease (PD). The mαSyn expression leads to the loss of dopaminergic neurons in the substantia nigra (SN) and consequent motor dysfunctions. Additionally, studies found that PD was accompanied by extensive neuroinflammation of SN. However, it remains unclear as to whether microglia participate in the mαSyn pathology. This issue is addressed by using AAV-mα-Syn (A30P-A53T) to overexpress the human mαSyn in the SN in view of establishing the PD model. Subsequently, minocycline (Mino) was used to inhibit microglia activity, and an interleukin-1 receptor (IL-1R1) antagonist was used to hinder the IL-1R1 function. Finally, immunohistochemistry was used to analyze phosphorylated αSyn (Ser129) and TH-positive cells in the SN. Dopamine levels were analyzed by high performance liquid chromatography. mαSyn overexpression in the SN induced motor dysfunction, decreased striatal dopamine levels, and increased pathological αSyn 12 weeks after AAV injection. The data demonstrated that inhibiting microglial activation or hindering IL-1R1 reversed the persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system, and development of Lewy body pathology caused by human mαSyn overexpression in the SN. Additionally, these findings indicate that neuroinflammation promotes the loss of neuronal cells.