Microglial clearance, neuroprotection and cognitive recovery via a novel synthetic sulfolipid in Alzheimer’s disease

Background: Microglial dysfunction has emerged as a critical factor in the Alzheimer’s Disease (AD), with innate immune dysregulation driving pathological progression. This growing understanding has shifted attention toward the therapeutic modulation of glial response as a means to restore immune balance and promote neuronal resilience. Increasing attention has also focused on small-molecules capable of reprogramming microglia toward a reparative, surveillance-competent phenotype that enhances Amyloid-β (Aβ) clearance while limiting detrimental neuroinflammation. In this context, we previously reported that Sulfavant A (SULF A), a novel synthetic sulfolipid, binds to Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and activates myeloid cells without inducing inflammatory hallmarks. Methods: The immunomodulatory properties of SULF A were characterized using biochemical, molecular, and cell biological approaches in primary murine microglia. The small modulatory molecule SULF A was synthetically produced in our laboratory. Functional assays included quantitative analyses of phagocytosis using standard beads and fluorescently labeled Aβ peptides, designed and synthesized considering tag emission and fiber aggregation. Aβ aggregation was characterized using biophysical and biochemical methods to ensure well-defined assemblies in microglial assays. To assess translational relevance, SULF A was evaluated at two distinct time points, before and after Aβ plaque deposition, in Tg2576 transgenic mice, a well-established AD model, to determine its neuroprotective potential and therapeutic efficacy. Results: We demonstrate that the small-molecule TREM2 ligand SULF A functions as an immunomodulator that reprograms microglia toward a reparative phenotype. It promotes a ramified and polarized microglial morphology associated with enhanced cellular motility, phagocytic capacity and clearance of neurotoxic Aβ peptides. SULF A upregulates arginase expression, downregulates inducible Nitric Oxide Synthase (iNOS), and redirects microglial metabolism toward tissue-protective functions. This phenotypic shift is characterized by increased TREM2 turnover and upregulation of CD68 and CCL2, without triggering classical inflammatory hallmarks. In vivo, SULF A enhances plaque‑associated microglial recruitment, reduces plaque burden, preserves midbrain dopaminergic neurons, and improves cognitive and motivational performance in Tg2576 mice. Conclusions: We propose that SULF A is a promising therapeutic small molecule that restores microglial homeostasis via an inflammation-sparing mechanism. It enhances amyloid clearance, preserves vulnerable neurons, and improves cognitive function in vivo. These findings support SULF A as a disease-modifying approach that extends beyond conventional plaque-targeting strategies in AD.