Identification of a novel class of small molecules for the treatment of Neurodegenerative diseases.

The triggering receptor expressed on myeloid cells 2 (TREM2) is a member of immunoglobulin superfamily mainly expressed by microglia. This receptor promotes microglial proliferation and survival, as well as regulating phagocytosis and metabolism, and is proposed to mediate a novel form of microglial anti-inflammatory activation. 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 and Parkinson disease (PD). In AD-related conditions, TREM2 interacts with lipoproteins, anionic lipids, and A?, which contributes to microglial metabolism remodelling, as well as promotes microglial phagocytosis of cell debris and A?. These effects support the hypothesis that TREM2 might play a protective role through regulating microglia polarization and be a potential target for AD prevention and treatment. Many proteins or compounds that bind to TREM2 have been reported, but the natural signal-transducing ligands of TREM2 present in the brain have not been identified. We recently reported a novel immunomodulatory sulfolipid named Sulfavant A (SULF-A), which primes maturation of dendritic cells (DC) towards a novel homeostasis-determining phenotype (homeDCs) by engagement of TREM2 (Manzo, 2017, doi: 10.1038/s41598-017-059698; Gallo, 2022, doi: 10.1007/s00018-022-04297-z). Preliminary results suggested the ability of this molecule to activate also microglial cells towards an unconventional non inflammatory state, prompting the idea that the investigation of TREM2 pathway may lay the groundwork for the development of a new class of drugs with therapeutic potential in neurodegenerative diseases, chronic-inflammation and cancer.