TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection.

Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 (TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration. We also find that TREM2 knockout mice exhibit an altered glial response following demyelination. TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris. In addition, human monocyte-derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis. Together, we highlight the central role of TREM2 signaling in remyelination and neuroprotection. These findings provide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuroprotective therapeutic targets for MS.

Wang Y ，Kyauk RV ，Shen YA ，Xie L ，Reichelt M ，Lin H ，Jiang Z ，Ngu H ，Shen K ，Greene JJ ，Sheng M ，Yuen TJ ... -  《-》

TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis.

Cignarella F ，Filipello F ，Bollman B ，Cantoni C ，Locca A ，Mikesell R ，Manis M ，Ibrahim A ，Deng L ，Benitez BA ，Cruchaga C ，Licastro D ，Mihindukulasuriya K ，Harari O ，Buckland M ，Holtzman DM ，Rosenthal A ，Schwabe T ，Tassi I ，Piccio L ... -  《-》

Trem2-deficiency aggravates and accelerates age-related myelin degeneration.

McCray TJ ，Bedford LM ，Bissel SJ ，Lamb BT ... -  《Acta Neuropathologica Communications》

Genetic models of cleavage-reduced and soluble TREM2 reveal distinct effects on myelination and microglia function in the cuprizone model.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell-surface immunoreceptor expressed on microglia, osteoclasts, dendritic cells and macrophages. 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, such as 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), knockout (TREM2-KO) and wild-type (WT) mice. The TREM2-sol mouse is a new model with selective elimination of plasma membrane TREM2 and a reduced expression of soluble TREM2. In the acute cuprizone model demyelination and remyelination events were reflected by a T2-weighted signal intensity change in magnetic resonance imaging (MRI), most prominently in the external capsule (EC). In contrast to WT and TREM2-IPD, TREM2-sol and TREM2-KO showed an additional increase in MRI signal during the recovery phase. Histological analyses of TREM2-IPD animals revealed no recovery of neuroinflammation as well as of the lysosomal marker LAMP-1 and displayed enhanced cytokine/chemokine levels in the brain. TREM2-sol and, to a much lesser extent, TREM2-KO, however, despite presenting reduced levels of some cytokines/chemokines, showed persistent microgliosis and astrocytosis during recovery, 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 without plasma membrane TREM2 and only soluble TREM2 had reduced phagocytic activity despite efficient lysosomal function, as observed in bone marrow-derived macrophages, leading to a dysfunctional phenotype with improper myelin debris removal, lack of remyelination and axonal pathology following cuprizone intoxication.

Beckmann N ，Neuhaus A ，Zurbruegg S ，Volkmer P ，Patino C ，Joller S ，Feuerbach D ，Doelemeyer A ，Schweizer T ，Rudin S ，Neumann U ，Berth R ，Frieauff W ，Gasparini F ，Shimshek DR ... -  《Journal of Neuroinflammation》

Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945.

Beckmann N ，Giorgetti E ，Neuhaus A ，Zurbruegg S ，Accart N ，Smith P ，Perdoux J ，Perrot L ，Nash M ，Desrayaud S ，Wipfli P ，Frieauff W ，Shimshek DR ... -  《Acta Neuropathologica Communications》