TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Multiple sclerosis (MS) disability stems from failed remyelination and neurodegeneration.
• Microglia and triggering receptor expressed on myeloid cells 2 (TREM2) are implicated in remyelination processes.

Purpose of the Study:

• To investigate the role of TREM2 in remyelination and neuroprotection within a focal demyelination model.
• To examine the impact of TREM2 deficiency on microglial function and glial response post-demyelination.

Main Methods:

• Utilized a focal brain demyelination model induced by lysolecithin injection in TREM2 knockout mice.
• Assessed persistent demyelination, neurodegeneration, and glial responses, including microglial migration and phagocytosis of myelin debris.
• Analyzed myelin debris phagocytosis in human monocyte-derived macrophages with a TREM2 mutation.

Main Results:

• TREM2 knockout mice showed persistent demyelination for over 6 weeks and significant neurodegeneration.
• TREM2 knockout microglia exhibited impaired migration and reduced phagocytosis of myelin debris.
• Human macrophages with a TREM2 mutation also displayed defective myelin debris phagocytosis.

Conclusions:

• TREM2 signaling plays a central role in effective remyelination and neuroprotection.
• Defects in TREM2 function contribute to chronic demyelination and axonal damage, relevant to MS pathogenesis.
• Targeting TREM2 signaling may offer novel therapeutic strategies for neuroprotection in MS.