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MEK1/2 activity modulates TREM2 cell surface recruitment.

Jason Schapansky1, Yelena Y Grinberg1, David M Osiecki2

  • 1AbbVie Inc, Cambridge Research Center, Cambridge, Massachusetts, USA.

The Journal of Biological Chemistry
|April 11, 2021
PubMed
Summary
This summary is machine-generated.

Researchers identified MEK1/2 inhibitors as a novel way to increase TREM2 protein on the surface of myeloid cells, potentially offering a new therapeutic strategy for Alzheimer's disease (AD). This finding reveals a previously unknown pathway regulating TREM2 activity.

Keywords:
Alzheimer’s diseaseMEKTREM2microglianeurodegenerationneuroinflammationphagocytosis

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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.