Identification of a novel class of small molecules for the treatment of TREM2-related neurodegenerative dysfunctions

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is an innate immune receptor expressed in the resident microglia cells of the central nervous system. In response to pathologic changes, TREM2 mediates rapidly the activation of microglia that, in turn, eliminate synapses and degenerating cells through phagocytosis. A number of TREM2 variants have been identified as risk factors for a wide array of neurodegenerative diseases (NDs), including Nasu-Hakola disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and FTD-like syndrome without bone involvement. Here we report on the identification of natureinspired synthetic small molecules capable to modulate the TREM2 function with a promising property to ameliorate ND pathogenesis. Our study has integrated approaches and methodology of chemical biology with cellular and molecular biology for the phenotypic and molecular characterization of TREM2-mediated mechanisms. This multidisciplinary approach allows the identification of a new class of sulfolipids (e.g. Sulfavant A) with a favourable role in microglia response via TREM2 activation. In particular, we found that murine primary microglia exposed to Sulfavant A (SULF-A) showed increased levels of TREM2 and arginase and low levels of pro-inflammatory markers (e.g. CD40 and CD86). Noteworthy, no production of nitric-oxide was detected in the supernatant of SULF-A-treated microglia culture. Moreover, flow cytometry analysis and immunocytochemistry proved increased phagocytosis in SULF-A treated-microglia compared to resting cells. Time-lapse observations supported rapid changes in cellular morphology from a ramified to ameboid form within 24 hours of the in vitro treatment. Collectively, these findings suggest that SULF-A activates primary microglia through a new non-inflammatory pathway. Further studies in neuron-microglia co-cultures are required to define whether and how SULF-A may modulate the crosstalk between neurons and microglia, both in healthy and ND conditions. We believe that the identification of compounds capable to stimulate TREM2 modulation and microglia activation could open new avenues to discover novel immune-related ND biomarkers and therapeutics.