The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

Soluble TREM2 (sTREM2) changes dynamically in the CSF of AD patients during progression of disease, peaking at the early symptomatic stages.

“Recently, soluble TREM2 (sTREM2), generated by the proteolytic cleavage of full length TREM2 by ADAM10 and ADAM17, was found to change dynamically in the CSF of AD patients during the progression of disease, peaking at the early symptomatic stages of the disease.211”

The TREM2 pathway can be targeted by specific antibodies or small molecules that regulate downstream signaling.

“The TREM2 pathway can be targeted by specific antibodies or small molecules that regulate downstream signaling.211”

These kinases are centrally involved in controlling cell metabolism, survival, proliferation, and phagocytosis.

“These kinases are centrally involved in controlling cell metabolism, survival, proliferation, and phagocytosis29,30.”

TREM2 engagement with ligands triggers phosphorylation of DAP12 ITAM and activates downstream kinases such as AKT, MAPK, and mTOR.

“TREM2 engagement with ligands triggers the phosphorylation of the DAP12 ITAM, subsequently initiating a cascade of activation of downstream kinases, such as AKT, MAPK, and mTOR29,30.”

TREM2 ligands include bacterial wall products, Aβ oligomers, lipoproteins, and anionic lipids such as phospholipids and sphingolipids.

“TREM2 ligands include a variety of molecules, such as bacterial wall products, Aβ oligomers, lipoproteins, and anionic lipids, such as phospholipids and sphingolipids29,32–35”

The opposite phenotypes observed in PLCG2 KO iMGs and Plcγ2-P522R KI mice support the notion to therapeutically stimulate TREM2 functions.

“The opposite phenotypes observed in PLCG2 KO iMGs and Plcγ2-P522R KI mice also support the notion to therapeutically stimulate TREM2 functions [6, 16, 17, 43].”

TREM2 expression is restricted to myeloid lineage, including dendritic cells and monocytes, as well as parenchymal macrophages residing in various tissues/organs, such as the lungs, bones and liver.

“TREM2 expression is restricted to myeloid lineage, including dendritic cells and monocytes, as well as parenchymal macrophages residing in various tissues/organs, such as the lungs, bones and liver [4, 23]”

TREM2 and PLCγ2 are critical for the proper maturation, maintenance and function of a range of immune and hematopoietic-lineage cells.

“These proteins are critical for the proper maturation, maintenance and function of a range of immune and hematopoietic-lineage cells [5, 23].”

TREM2 function is regulated via interactions and crosstalk with other receptors, including the AD risk hits CD33, and the Ms4A gene-cluster products.

“TREM2 function is regulated via interactions and crosstalk with other receptors, including the AD risk hits CD33, and the Ms4A gene-cluster products [23, 59].”