Intracellular trafficking of TREM2 is regulated by presenilin 1

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. Neurodegenerative disease: Finding a new trigger Researchers have identified a new interaction between two molecules that may clarify development of some neurodegenerative diseases. The TREM2 receptor activates microglia, immune cells in the brain, but it must be on the cell surface to function correctly. Mutations in TREM2 that alter its location have been implicated in development of Alzheimer's disease (AD) and Parkinson's disease but TREM2 transport within cells remains poorly understood. Researchers led by Huaxi Xu of the Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA, and Qi Wang of the Guangzhou University of Chinese Medicine investigated TREM2 transport by searching for proteins that interact with it. They found that presenilin 1, which has also been implicated in AD, regulates TREM2 transport and affects activation of microglia. These results may help to identify a new target for development of AD treatments.