Microglia Process α-Synuclein Fibrils and Enhance their Pathogenicity in a TREM2-Dependent Manner

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Parkinson's disease (PD) involves misfolded alpha-synuclein (α-syn) aggregation and cell-to-cell transmission.
• Microglia, the brain's immune cells, are activated in PD patients, suggesting a role in disease progression.
• Mechanisms of pathological α-syn cell-to-cell spread remain incompletely understood.

Purpose of the Study:

• To investigate the role of microglia in the cell-to-cell transmission of pathological α-syn.
• To elucidate the molecular mechanisms by which microglia contribute to α-syn spread in PD.
• To identify potential therapeutic targets for blocking α-syn pathology propagation.

Main Methods:

• Utilized mouse models injected with α-syn fibrils.
• Depleted microglia to assess their impact on α-syn pathology spread.
• Investigated the role of triggering receptor expressed on myeloid cells 2 (TREM2) and asparagine endopeptidase (AEP) in microglia-mediated α-syn processing.
• Examined the effects of TREM2 and AEP knockout on α-syn endocytosis and cleavage.

Main Results:

• Microglia phagocytose α-syn fibrils, generating more toxic species.
• TREM2 mediates the phagocytosis of α-syn fibrils by microglia.
• Asparagine endopeptidase (AEP) cleaves endocytosed α-syn fibrils into truncated forms with enhanced seeding activity.
• Depletion of microglia, knockout of TREM2, or knockout of AEP significantly slowed the spread of α-syn pathology.

Conclusions:

• Microglia actively contribute to the spread of pathological α-syn in the brain.
• TREM2-mediated phagocytosis and subsequent AEP-mediated cleavage are critical steps in microglia's role in α-syn propagation.
• Targeting TREM2-dependent phagocytosis or AEP-mediated cleavage represents a potential therapeutic strategy to attenuate Parkinson's disease progression.