ABSTRACT
Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's Disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.Significance Statement Multiple TREM2 agonist antibodies are investigated in mouse models of Alzheimer's Disease and Multiple Sclerosis. Despite agonism in culture models and after acute dosing in mice, antibodies do not show benefit in overall AD pathology and worsen recovery after demyelination.
ABSTRACT
Lipid derived mediators contribute to inflammation and the sensing of pain. The contributions of omega-6 derived prostanoids in enhancing inflammation and pain sensation are well known. Less well explored are the opposing anti-inflammatory and analgesic effects of the omega-6 derived epoxyeicosatrienoic acids. Far less has been described about the epoxidized metabolites derived from omega-3 long chain fatty acids. The epoxide metabolites are turned over rapidly with enzymatic hydrolysis by the soluble epoxide hydrolase being the major elimination pathway. Despite this, the overall understanding of the role of lipid mediators in the pathology of chronic pain is growing. Here, we review the role of long chain fatty acids and their metabolites in alleviating both acute and chronic pain conditions. We focus specifically on the epoxidized metabolites of omega-6 and omega-3 long chain fatty acids as well as a novel strategy to modulate their activity in vivo.
