Vps35-dependent recycling of Trem2 regulates microglial function

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Triggering receptor expressed on myeloid cells 2 (Trem2) is crucial for microglial function in the central nervous system.
• Trem2's role in Alzheimer's disease (AD) pathogenesis is linked to microglial inflammatory responses and phagocytosis.
• The intracellular trafficking mechanisms of Trem2 are not fully understood.

Purpose of the Study:

• To investigate the intracellular trafficking pathways of Trem2 in microglia.
• To determine the role of Vps35/retromer complex in Trem2 trafficking and microglial function.
• To examine the impact of the AD-associated R47H Trem2 mutation on its trafficking and stability.

Main Methods:

• Studied Trem2 endocytosis and recycling in microglia.
• Utilized Vps35 knockdown to assess Trem2 accumulation and degradation.
• Analyzed lipopolysaccharide (LPS)-induced inflammatory markers (iNOS, IL-6) in response to Vps35 manipulation and Trem2 overexpression.
• Investigated the interaction and stability of wild-type and R47H Trem2.

Main Results:

• Trem2 undergoes clathrin-dependent endocytosis and recycling via Vps35, not Rab11.
• Vps35 knockdown causes Trem2 lysosomal accumulation without degradation.
• Vps35 deficiency exacerbates LPS-induced iNOS and IL-6 production, which Trem2 overexpression can mitigate.
• The R47H Trem2 mutant shows impaired interaction with Vps35 and reduced stability.

Conclusions:

• Vps35/retromer complex mediates Trem2 recycling, regulating microglial inflammatory responses.
• Impaired Trem2 trafficking due to the R47H mutation may contribute to Alzheimer's disease development.
• Understanding Trem2 trafficking is critical for developing therapeutic strategies for AD.