TREM2 supports neuronal protection and microglial reactivity independently of affecting misfolded protein deposition in chronic neurodegenerative prion disease

TREM2 (triggering receptor expressed on myeloid cells-2) variants have been identified as risk factors for neurodegenerative disease including Alzheimer’s disease. TREM2 is a cell surface receptor on microglia that regulates homeostatic and immunomodulatory functions including phagocytosis of apoptotic debris and the resolution of damage-associated inflammation. It remains unclear how TREM2 may mediate an influence on neurodegenerative disease, particularly in relation to key neuropathological hallmarks such as neuronal loss and proteinopathy. We used the ME7 prion disease model to assess the role of TREM2 in the progression and pathology of neurodegenerative disease. Prion diseases are characterised by the accumulation of misfolded prion protein and provide a highly tractable platform to determine if TREM2 has disease-modifying effects. Trem2-/- and wild type mice were inoculated intracerebrally with mouse-passaged ME7 scrapie prions and effects on CNS disease pathogenesis determined. Although the accumulation of prion disease-specific PrP was similar in the brains of mice from each group, the severity of the neuropathology was increased in Trem2-/- mice. Morphometric analysis of the microglia also indicated blunted disease-induced reactivity in the brains of infected Trem2-/- mice compared to wild type (WT) controls. The expression of genes involved in myelination were reduced in prion-infected Trem2-/- mice compared to infected WT mice. We conclude that during infection of the brain with prions, TREM2 supports microglial reactive changes that are associated with resilience to neuronal loss independently of affecting misfolded PrP deposition. These data imply that TREM2 status may be an important influence on the downstream response to CNS proteinopathy that alters the susceptibility of neurons and brain tissue to proteinopathy-induced degenerative changes. Transcriptional profiles of brain tissue from WT and Trem2-/- mice inoculated intracerebrally with either normal brain homogenate (NBH) or brain homogenate from mice terminally infected with mouse-passaged ME7 scrapie prion strain. Dataset includes a total of of 14 samples, including biological replicates for two different genotypes (WT and Trem2-/-) and 2 treaments (NBH and ME7).