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

Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell-surface immunoreceptor expressed on microglia, osteoclasts and monocytes/macrophages. In humans, homozygous loss-of-function mutation carriers exhibit bone cysts and fractures with an early-onset frontal lobe syndrome and progressive presenile dementia known as Nasu-Hakola. Neuropathological findings include myelin/neuronal loss and neuroinflammation. Heterozygous loss-of-function mutation in TREM2 has been associated with several neurodegenerative diseases like Alzheimer`s disease and Frontotemporal Dementia. We investigated the involvement of soluble and cleavage-reduced TREM2 on central myelination processes by using different gene-modified animals expressing (cleavage-reduced (TREM2-IPD), soluble-only (TREM2-sol), knock-out (TREM2-KO) TREM2and wildtype (WT) mice in the cuprizone model.. In the acute cuprizone model all genotypes showed demyelination detected by T2-weighted signal intensity increase in Magnetic resonance imaging (MRI), most prominent in the external capsule (EC) and less in the corpus callosum. In the 4-week recovery phase a partial signal reduction in WT and TREM2-IPD was observed, while in TREM2-sol and TREM2-KO showed an increase in MRI signal in the EC. In TREM2-IPD histology revealed no recovery of neuroinflammation as well as of the lysosomal marker LAMP-1, which was also evidenced in enhanced cytokine/chemokine levels. This persistent microgliosis and astrocytosis was also observed in TREM2-sol, to a lesser extent in TREM2-KO during recovery with both homeostatic (TMEM119) as well as activated (LAMP-1) microglia markers increased. An increase in cytokines/chemokines was not evident. This was accompanied, specifically in the EC with no myelin recovery, appearance of myelin debris and axonal pathology, while oligodendrocytes recovered. In the chronic cuprizone model TREM2-IPD displayed sustained microgliosis and enhanced remyelination in the recovery phase. Taken together, our data suggest that sustained microglia activation leads to increased remyelination, whereas microglia without membrane-functional or complete loss of TREM2 results in a dysfunctional phenotype with improper myelin debris removal, lack of remyelination and axonal pathology.