Diminished age-related loss of neurons, neuroinflammation and oxidative stress in Triggering Receptor Expressed on Myeloid cells-2 deficient mice

Triggering receptor expressed on myeloid cells-2 (TREM2) and its immunoreceptor tyrosine-based activation motif-containing adaptor molecule DAP12/TYROBP are involved in microglial functions such as homeostasis, response to pathogens, migration, phagocytosis, release of inflammatory factors and oxidative burst. Genetic variants or mutations of TREM2 and TYROBP have been linked to inflammatory neurodegenerative diseases such as Nasu-Hakola disease or Alzheimer´s disease, both being associated with aging.The typical aging process goes along with neuroinflammation and mild loss of neurons, but the exact contribution of TREM2 to aging is still unclear. Therefore, we first checked for neuronal loss in two different brain regions that are affected during aging and in different age-related neurodegenerative diseases – hippocampal CA3 region and substantia nigra pars compacta. In both brain regions, less age-related neuronal loss was observed in TREM2 KO mice. Transcriptome analysis of the brains revealed 211 differentially expressed genes between 24 months old TREM2 KO and wildtype animals. Most differentially expressed genes were involved in pathways of complement activation and oxidative stress response. Interestingly, transcription of microglial markers, pro-inflammatory cytokines, oxidative stress markers, phagocytic markers and complement components were decreased in 24 months old TREM2 KO mice. Moreover, the number of microglia as well as the expression levels of the microglial markers Iba1 and Cd68 were decreased in 24 months old TREM2 KO mice as revealed by microscopy. Primary microglia cultures obtained from TREM2 KO mice showed reduced phagocytosis of beads and less production of superoxide after challenge with neural debris. Thus, TREM2 might trigger radical production with detrimental effects during aging. Data show that TREM2 contributes to age-related neuroinflammation and loss of neurons and suggest that TREM2 could also have detrimental functions in the non-diseased brain.