Soluble TREM2 induces microglia dysfunction and brain damage while cleavage-reduced TREM2 shows sustained microglia activation with enhanced myelination in the cuprizone model

Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell-surface immunoreceptor expressed on microglia, osteoclasts, dendritic cells andmacrophages. Heterozygous loss-of-function mutations in TREM2, including mutations enhancing shedding form the cell-surface, have been associated with myelin/neuronal loss and neuroinflammation in neurodegenerative diseases like Alzheimer`s disease and Frontotemporal Dementia. Using the cuprizone model, we investigated the involvement of soluble and cleavage-reduced TREM2 on central myelination processes in cleavage-reduced (TREM2-IPD), soluble-only (TREM2-sol), knock-out (TREM2-KO) and wildtype (WT) mice. In the acute cuprizone model consisting of a five-week intoxication by the copper chelator followed by a four-week recovery all genotypes showed demyelination at the peak of disease reflected by a T2-weighted signal intensity increase in magnetic resonance imaging (MRI), most prominently in the external capsule (EC). During the recovery phase a partial signal reduction in WT and TREM2-IPD was observed, while TREM2-sol and TREM2-KO showed an additional increase in MRI signal in the EC. At week 9 histology revealed no recovery of neuroinflammation as well as of the lysosomal marker LAMP-1 in TREM2-IPD animals, which also displayed enhanced cytokine/chemokine levels in the brain. Despite presenting reduced levels of some cytokines/chemokines, persistent microgliosis and astrocytosis at week 9 was likewise observed in TREM2-sol and to a much lesser extent in TREM2-KO, with both homeostatic (TMEM119) as well as activated (LAMP-1) microglia markers increased. This was accompanied, specifically in the EC, by no myelin recovery, with appearance of myelin debris and axonal pathology, while oligodendrocytes recovered. In the chronic model consisting of 12-week cuprizone administration followed by 3-week recovery TREM2-IPD displayed sustained microgliosis and enhanced remyelination in the recovery phase. Taken together, our data suggest that sustained microglia activation led to increased remyelination, whereas microglia with only soluble TREM2 had reduced phagocytic activity despite efficient lysosomal function leading to a dysfunctional phenotype with improper myelin debris removal, lack of remyelination and axonal pathology following cuprizone intoxication.