MEK1/2 activity modulates TREM2 cell surface recruitment

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Rare variants in the TREM2 gene are linked to increased Alzheimer's disease (AD) risk.
• TREM2 mutations often result in partial loss of function, suggesting therapeutic benefits from enhancing TREM2 activity.
• Druggable targets to modulate microglial TREM2 surface expression remain largely unknown.

Purpose of the Study:

• To identify small molecule compounds that can enhance TREM2 protein expression at the cell surface of human myeloid cells.
• To uncover novel pathways regulating TREM2 activity for potential therapeutic intervention in AD.

Main Methods:

• Screening of small molecule compounds with known pharmacology in human myeloid cells.
• Utilizing MEK1/2 and ERK kinase inhibitors to investigate TREM2 regulation pathways.
• Employing siRNA knockdown experiments to confirm the role of MEK1/2.
• Testing cytokine priming (IFN-gamma) in iPSC-derived microglia to enhance TREM2 recruitment.

Main Results:

• Inhibitors of MEK1/2 kinases significantly increased cell surface TREM2 protein, identifying a new regulatory pathway.
• ERK inhibitors did not show the same effect, suggesting noncanonical MEK signaling in TREM2 trafficking.
• MEK1/2 downregulation was confirmed as necessary for TREM2 recruitment via siRNA.
• IFN-gamma priming combined with MEK inhibitor treatment enhanced TREM2 recruitment in iPSC-derived microglia.

Conclusions:

• This study identifies the first known mechanisms to increase surface TREM2 protein and TREM2-regulated function in human myeloid cells.
• MEK1/2 signaling plays a crucial role in regulating TREM2 activity and trafficking.
• These findings offer a potential therapeutic avenue for AD by targeting the MEK pathway to enhance TREM2 function.