Abstract
Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson’s disease. In the brain, TREM2 is highly expressed on the cell surface of microglia, where it can transduce signals to regulate microglial functions such as phagocytosis. To date, mechanisms underlying intracellular trafficking of TREM2 remain elusive. Mutations in the presenilin 1 (PS1) catalytic subunit of the γ-secretase complex have been associated with increased generation of the amyloidogenic Aβ (amyloid-β) 42 peptide through cleavage of the Aβ precursor amyloid precursor protein. Here we found that TREM2 interacts with PS1 in a manner independent of γ-secretase activity. Mutations in TREM2 alter its subcellular localization and affects its interaction with PS1. Upregulation of PS1 reduces, whereas downregulation of PS1 increases, steady-state levels of cell surface TREM2. Furthermore, PS1 overexpression results in attenuated phagocytic uptake of Aβ by microglia, which is reversed by TREM2 overexpression. Our data indicate a novel role for PS1 in regulating TREM2 intracellular trafficking and pathophysiological function.
Highlights
We found that WT, R47H and T96K triggering receptor expressed on myeloid cells 2 (TREM2) predominantly localized in the Golgi apparatus, as seen by high colocalization coefficients observed with the Golgi marker TGN46, (Figures 2a and c), whereas T66M TREM2 primarily localized in the endoplasmic reticulum (ER) as indicated by colocalization with the ER marker PDI (Figures 2b and c)
TREM2 has been previously reported to be a substrate of the γsecretase complex,[31,33] which suggests that TREM2 proteolysis could influence cell surface TREM2 distribution and function
Since total full-length TREM2 levels were unaffected by presenilin 1 (PS1) overexpression, this suggests that PS1 upregulation alone cannot enhance TREM2 proteolysis
Summary
TREM2 is a type I transmembrane protein comprising an extracellular, Ig-like V-type domain; a transmembrane domain; and an intracellular domain lacking any obvious signaling motifs (Figure 1f). Signal transduction induced by ligand engagement, for example, ApoE,[14,15,16] with the TREM2 extracellular domain is mediated through its association with. DNAX-activating protein of 12 kDa (DAP12), which triggers intracellular signals through an immunoreceptor tyrosinebased activation motif.[17,18] TREM2 expression is primarily found in microglia, and mounting evidence indicates that TREM2 signaling is important in the regulation of microglial phagocytosis and inflammatory cytokine production.[19,20,21,22,23,24,25,26,27,28,29,30] Several disease-associated TREM2 mutations have been reported to reduce cell surface TREM2 distribution and impair microglial phagocytic function.[31,32] the presence of TREM2 at the cell surface is important in mediating microglial functions such as phagocytosis. Aberrant Aβ accumulation can trigger a cascade of neurodegenerative events including
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