TREM2 mediated microglial dysfunction in a model of demyelination

Identification: O'Loughlin, Elaine



TREM2 mediated microglial dysfunction in a model of demyelination
Elaine O'Loughlin1, Sophia Bardehle1, Anna-Mari Kärkkäinen3, Teija Parkkari3, Kimmo Lehtimäki3, Nicholas Thomas Gatto2, Anjali Patel2, Gonzalo Zeballos1, Antti Nurmi3, Geoffrey Varty4, Thomas Rosahl4, Matthew E. Kennedy1 and Christian Mirescu1
1Discovery Neuroscience, Merck & Co.  Boston, MA; 2Pathology Department, Merck & Co., West Point, PA; 3Charles River Discovery ServicesKuopio, Finland; 4External In Vivo Pharmacology, Merck & Co., Kenilworth, NJ
Microglia are the brain's resident immune cells that maintain tissue homeostasis and react to insults and injury by initiating an inflammatory reaction. Trem2, triggering receptor expressed on myeloid cells 2, is a microglial surface receptor known to participate in phagocytosis, cell migration, cytokine release and proliferation. Interest in Trem2 biology has grown as human studies have implicated loss-of-function Trem2 variants (R47H, H157Y and R62H) with increased risk of Alzheimer's disease (AD). In vivo data has demonstrated that Trem2 mutation leads to exacerbated neuropathology, demyelination and defective microglial function. We established a model of demyelination using the copper chelator, cuprizone, to study Trem2 in microglial biology. Wild type (WT) and Trem2-/- male mice aged 9-11 weeks were treated with cuprizone (150 mg/kg, po, bid) over 5 weeks. Preliminary data showed that Trem2-/--treated mice were more susceptible to cuprizone challenge and exhibited significant weight loss and mortality in comparison to WT-treated controls. Analysis of locomotor function following cuprizone treatment revealed that Trem2-/-mice had significantly decreased rotarod performance at end stage compared with WT controls. Diffusion tensor imaging (DTI) revealed that both genotypes had highly robust demyelination and changes in brain structures, however at study end, Trem2-/--treated mice had significantly reduced fractional anisotropy and mean diffusion in the corpus callosum (CC) relative to wild type mice. Histopathological analyses using luxol fast blue were consistent with the DTI findings, as more severe demyelination was observed in Trem2-/--treated mice, compared with WT-treated controls. Trem2-/--treated mice exhibited significantly fewer Iba1+ cells and reduced cell proliferation after cuprizone challenge relative to WT-treated mice. Moreover, Trem2-/--treated mice have significantly increased degraded myelin basic protein (dMBP) in the CC, which suggests a failure of cellular proliferation and debris clearance. Taken together, the data suggests that microglia phenotypes and functions are significantly disrupted in the absence of Trem2, further emphasizing the importance of Trem2 in microglial biology. In conclusion, Trem2 function and likely signaling plays a key role in the adaptive response of microglia. Targeting modulation of Trem2 signaling in microglia may represent a new therapeutic avenue to restore and rescue CNS homeostasis and reduce the inflammatory burden in demyelinating and neurodegenerative diseases.



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