18. TREM2 Signalling Pathway 

 

According to Deczkowska A et al., 2020 “TREM2 contains an extracellular domain, which comprises a single V-type immunoglobulin domain, a small ectodomain, a single transmembrane helix and a small cytosolic tail with the absence of ability for any signal transduction or trafficking motifs”(Deczkowska A et al., 2020)”.

 

Induction of downstream intracellular signaling pathway occurs as the communication of TREM2 ligand with coreceptors DAP12 (DNAX Activation Protein 12), which is also called TYROBP (TYRO protein tyrosine kinase binding protein), and DAP10 takes place and ultimately they become phosphorylated (Deczkowska A et al., 2020).

 

DAP10 through deployment of PI3K (phosphatidylinositol 3-kinase) activates the downstream signal transduction and DAP12 plays role in inducing of Syk (spleen tyrosine kinase) (Deczkowska A et al., 2020).

 

It is known that the induction of AKT1 a serine/ threonine protein kinase and ERK (Extracellular signal Regulated Kinase) takes place through DAP10, however, DAP12 plays role in calcium deployment in mouse macrophages (Otero K et al., 2012) (Peng Q et al,. 2010) (Ulland  T K. et al., 2017) (Deczkowska A et al., 2020).

 

Furthermore, TREM2 can interrelate with Aβ (β-amyloid) oligomers in the brains of AD (Alzheimer’s Disease) patients (Zhong L et al., 2018) (Deczkowska A et al., 2020). In mouse microglia (the brain’s myeloid cells) the level of APOE (Apolipoproteins) in answer to AD pathology is raised., and LPL (Lipoproteins) production, is augmented as a result of TREM2 induction (Keren-Shaul H et al., 2017) (Deczkowska A et al., 2020). APOE is essential for preservation of microglia phenotype, which is known to be reliant on TREM2 (Krasmann S et al., 2017) (Ulrich J D et al., 2018) (Deczkowska A et al., 2020).

 

TREM2 Signalling Pathway References

 

1.        Deczkowska, A., Weiner, A. & Amit, I. The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway. Cell 181, 1207–1217 (2020).

2.        Keren-Shaul, H. et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276-1290.e17 (2017).

3.        Krasemann, S. et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity 47, 566-581.e9 (2017).

4.        Otero, K. et al. TREM2 and β-Catenin Regulate Bone Homeostasis by Controlling the Rate of Osteoclastogenesis. J. Immunol. 188, 2612–2621 (2012).

5.        Peng, Q. et al. TREM2- and DAP12-Dependent Activation of PI3K Requires DAP10 and Is Inhibited by SHIP1. Sci. Signal. 3, (2010).

6.        Ulland, T. K. et al. TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease. Cell 170, 649-663.e13 (2017).

7.        Ulrich, J. D. et al. ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 215, 1047–1058 (2018).

8.        Zhong, L. et al. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). Mol. Neurodegener. 13, 15 (2018).