Disease relevance of TREM2

• In living human microglia CHME-5 and glioblastoma T98G cells, activation of TREM2 by its specific antibody induced [Ca2+]i responses, documenting its surface expression and functioning [1].
• Here we show that loss of function mutations in DAP12 and TREM2 result in an inefficient and delayed differentiation of osteoclasts with a remarkably reduced bone resorption capability in vitro [2].
• The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2 [3].
• Remarkably, TREM2 deficiency leads to a severe disease that is characterized by bone cysts and demyelination of the central nervous system, which results in dementia, implying that the function of TREM2 extends beyond the immune system [4].

Psychiatry related information on TREM2

• Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia [1].
• Recently, it has been shown that genetic defects of human DAP12/KARAP and TREM-2 result in a rare syndrome characterized by bone cysts and presenile dementia called Nasu-Hakola disease [5].

High impact information on TREM2

• DAP12 is a transmembrane adaptor protein that associates with the cell surface receptor TREM2 [2].
• DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features [2].
• The DAP12-TREM2 complex is involved in the maturation of dendritic cells [2].
• We have earlier characterized the molecular genetic background of PLOSL by identifying mutations in two genes, DAP12 and TREM2 [2].
• A TREM-2 Fc fusion protein bound to macrophages, indicating that macrophages express a TREM-2 ligand [6].

Biological context of TREM2

• Surface expression of TREM2, low in resting CHME-5 and T98G cells, increases significantly and transiently (60 min) when cells are stimulated by ionomycin, as revealed by both surface biotinylation and surface immunolabeling [1].
• Recently, molecular analysis of affected families revealed mutations in the DAP12 (TYROBP) or TREM2 genes, providing an interesting example how mutations in two different subunits of a multi-subunit receptor complex result in an identical human disease phenotype [7].
• Two healthy subjects heterozygous for one mutated TREM2 allele showed a deficit of visuospatial memory associated with hypoperfusion in the basal ganglia, whereas the homozygotes for the wild-type allele of TREM2 did not show any abnormalities [8].
• TREM2 RNA interference (RNAi) was used to disrupt expression of TREM2 in pre-osteoclasts [9].
• Moreover, mutation scanning of the five exons of TREM2 failed to detect the presence of novel polymorphisms [10].

Anatomical context of TREM2

• TREM2 forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells [11].
• Our results provide the first information about the expression, distribution (mostly intracellular) and functioning of TREM2/DAP12 system in nerve cells, a necessary step in the understanding of the cellular mechanisms affected in polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy [1].
• Also, the possible roles of the DAP12/TREM2 signaling pathway in microglia and osteoclasts in humans are just beginning to be elucidated [7].
• In addition to triggering receptor expressed on myeloid cells (TREM)-1 and TREM2, the cluster contains NKp44, a triggering receptor whose expression is limited to NK cells [12].
• TREM1 and TREM2 activate myeloid cells by signalling through the adaptor protein DAP12 [4].

Analytical, diagnostic and therapeutic context of TREM2

• We performed a functional neuroimaging (99mTc-ECD SPECT) and neuropsychological study of healthy members of an Italian family carrying a mutation in the TREM2 gene [8].
• MATERIALS AND METHODS: We generated monoclonal anti-mouse TREM2 antibodies (mAb), analyzed pre-osteoclasts and mature OCs for TREM2 surface expression, and determined the effect of antibody ligation on in vitro OC differentiation, resorption, and migration [9].

References