MEK1/2 activity modulates TREM2 cell surface recruitment

Abstract

Rare sequence variants in the microglial cell surface receptor TREM2 have been shown to increase the risk for Alzheimer’s disease (AD). Disease-linked TREM2 mutations seem to confer a partial loss of function, and increasing TREM2 cell surface expression and thereby its function(s) might have therapeutic benefit in AD. However, druggable targets that could modulate microglial TREM2 surface expression are not known. To identify such targets, we conducted a screen of small molecule compounds with known pharmacology using human myeloid cells, searching for those that enhance TREM2 protein at the cell surface. Inhibitors of the kinases MEK1/2 displayed the strongest and most consistent increases in cell surface TREM2 protein, identifying a previously unreported pathway for TREM2 regulation. Unexpectedly, inhibitors of the downstream effector ERK kinases did not have the same effect, suggesting that noncanonical MEK signaling regulates TREM2 trafficking. In addition, siRNA knockdown experiments confirmed that decreased MEK1 and MEK2 were required for this recruitment. In iPSC-derived microglia, MEK inhibition increased cell surface TREM2 only modestly, so various cytokines were used to alter iPSC microglia phenotype, making cells more sensitive to MEK inhibitor-induced TREM2 recruitment. Of those tested, only IFN-gamma priming prior to MEK inhibitor treatment resulted in greater TREM2 recruitment. These data identify the first known mechanisms for increasing surface TREM2 protein and TREM2-regulated function in human myeloid cells and are the first to show a role for MEK1/MEK2 signaling in TREM2 activity.

Single-cell-led drug repurposing for Alzheimer’s disease

“…MEK inhibitors selumetinib and trametinib could also possibly act on AD-associated neuroinflammation. Since TREM2 loss of function is one of the strongest known genetic AD risk factors, the discovery that MEK inhibition was able to raise TREM2 cell surface expression and function indicates opportunities for therapeutic intervention with these agents 67 . Sunitinib, which inhibits several tyrosine kinase receptors, has been previously associated to AD therapy with different mechanisms.…”

Screening Techniques for Drug Discovery in Alzheimer’s Disease

“…This device provides quantitative, kinetic, live-cell imaging and analysis which showed an increase in the expression of cell surface TREM2 protein. 50 Many hits showed an increase in both TREM2 and CD33 and are not included in the research since they are likely to be involved in mechanisms that stimulate cell surface protein in general. They have identified that inhibitors of kinases MEK1/2 display the strongest and most consistent increase in TREM2 protein.…”

“…Targets of small molecules from various compound libraries were screened on human myeloid cells (THP1-1) using Cellomics ArrayScan VTI HCS Reader. This device provides quantitative, kinetic, live-cell imaging and analysis which showed an increase in the expression of cell surface TREM2 protein . Many hits showed an increase in both TREM2 and CD33 and are not included in the research since they are likely to be involved in mechanisms that stimulate cell surface protein in general.…”