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

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Parkinson's disease (PD) involves dopaminergic neuron loss, alpha-synuclein (α-syn) accumulation, and microglial activation.
• Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function; TREM2 variant R47H is a PD risk factor.
• The precise role of TREM2 in regulating microglia during PD pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of TREM2 in microglial function, α-syn pathology, and neurodegeneration in Parkinson's disease models.
• To elucidate the molecular mechanisms by which TREM2 influences microglial responses in PD.

Main Methods:

• Constructed PD cell and animal models using α-syn preformed fibrils.
• Utilized siRNA and lentiviral methods to modulate TREM2 levels in cells.
• Employed TREM2 knockout and lentiviral overexpression in mice to assess TREM2's impact on microglial function, α-syn pathology, and dopaminergic neuron loss.

Main Results:

• Microglia demonstrated concentration- and time-dependent phagocytosis and degradation of α-syn aggregates.
• TREM2 expression was upregulated in PD models.
• TREM2 deficiency exacerbated α-syn spread, reduced microglial reactivity, and increased dopaminergic neuron loss.
• TREM2 overexpression promoted reactive microglial aggregation.
• Reduced TREM2 impaired microglial phagocytosis and proliferation but enhanced autophagy via the PI3K/AKT/mTOR pathway.

Conclusions:

• TREM2 signaling is essential for maintaining microglial phagocytosis, proliferation, and reactivity in PD.
• TREM2 stabilizes autophagy and proliferation through the PI3K/AKT/mTOR pathway in the context of PD.
• Modulating TREM2 levels presents a potential therapeutic avenue for Parkinson's disease treatment.