TREM2 signaling in Parkinson's disease: Regulation of microglial function and α-synuclein pathology

Background: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, abnormal accumulation of α-synuclein (α-syn), and microglial activation. Triggering receptor expressed on myeloid cells 2 (TREM2) regulates multiple functions of microglia in the brain, and several studies have shown that TREM2 variant R47H is a risk factor for PD. However, the regulation of microglia by TREM2 in PD remains poorly understood.

Methods: We constructed PD cell and animal models using α-syn preformed fibrils. siRNA knockdown and lentiviral overexpression were used to perturb TREM2 levels in cells, and TREM2 knockout mice and lentiviral overexpression was used in animal models to investigate the effects of TREM2 on microglial function, α-syn-related pathology, and dopaminergic neuron degeneration.

Results: Microglia phagocytosed α-syn preformed fibrils in a concentration- and time-dependent manner, with some capacity to degrade α-syn aggregates. TREM2 expression increased in PD. In the context of PD, TREM2 knockout mice exhibited worsened pathological α-syn spread, decreased microglial reactivity, and increased loss of TH-positive neurons in the substantia nigra compared to wild-type mice. TREM2 overexpression enhanced reactive microglial aggregation towards the pathological site. Cellular experiments revealed that reduced TREM2 impaired microglial phagocytosis and proliferation, but enhanced Autophagy via the PI3K/Akt/mTOR pathway.

Conclusion: TREM2 signaling in PD maintains microglial phagocytosis, proliferation, and reactivity, stabilizing Autophagy and proliferation via the PI3K/Akt/mTOR pathway. Regulating TREM2 levels may be beneficial in PD treatment.

Alpha-synuclein; Microglia; PI3K-AKT-mTOR pathway; Parkinson’s disease; TREM2.