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

Studies indicate that mutant alpha-synuclein (m alpha Syn) is involved in the pathogenesis of Parkinson's disease (PD). The m alpha Syn 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 m alpha Syn pathology. This issue is addressed by using AAVm alpha-Syn (A30P-A53T) to overexpress the human m alpha Syn 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 alpha Syn (Ser129) and TH-positive cells in the SN. Dopamine levels were analyzed by high performance liquid chromatography. m alpha Syn overexpression in the SN induced motor dysfunction, decreased striatal dopamine levels, and increased pathological alpha Syn 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 m alpha Syn overexpression in the SN. Additionally, these findings indicate that neuroinflammation promotes the loss of neuronal cells.