Menopause triggers microglia-associated neuroinflammation in Parkinson’s disease

Abstract

Microglia, the immune cells of brain, can drive neurodegenerative diseases like Parkinson’s disease (PD). The resting microglia can polarize into two extremes, either proinflammatory M1 or anti-inflammatory M2 phenotype under a specific microenvironment. Different transcriptional factors and the release of various cytokines characterize these states. The released proinflammatory markers from M1 microglia lead to neuroinflammation that ultimately causes irreversible loss of dopaminergic neurons in PD patients, on the contrary, the M2 microglia possess neuroprotective activity. PD is caused by aggregation and misfolding of α-synuclein in the affected dopaminergic neurons. The misfolded α-synuclein is cytotoxic and can propagate like a prion from one cell to the other, acting like a template, that can initiate the conversion of normal proteins into abnormal conformation. The extracellular α-synuclein can interact and polarize the microglia into the M1 phenotype resulting in inflammation, thereby driving the progression of PD. The progression of neuroinflammation-mediated neurodegeneration in PD is seen higher in menopausal women; likely due to the low circulating estrogen levels. Estrogen hormones possess neuroprotective activity, and one of the ways is that they can polarize the microglia into M2 phenotypes and reduce α-synuclein-mediated microglial activation. A detailed understanding of the signaling mechanisms underlying microglial polarization between M1 and M2 phenotypes is crucial for identifying druggable targets to reduce PD symptoms, including in menopausal women.