Galectin-3 deletion modulates microglial phenotype and Aβ response via TREM2 activation while attenuating neuroinflammation

Summary Galectin-3 (Gal3) is a regulator of microglial activation implicated in Alzheimer’s disease (AD). However, Gal3 role in modulating microglial phenotype towards amyloid-beta (Aβ) remains poorly understood. We demonstrate that Gal3 affects several microglial functions and binds Aβ fibrils with high affinity, stabilizing aggregation intermediates that alter fibril kinetics and morphology. Furthermore, Gal3 deletion affects the direct relationship between microglia and Aβ, reducing its uptake and increasing its compaction. AlphaFold modeling predicts direct Gal3-TLR4 interactions, suggesting a molecular link to inflammatory pathways. In vivo, Gal3 deletion reduces Aβ plaque burden in APP mice while suppressing interferon-alpha signaling and the neurodegenerative microglial (MGnD) phenotype. Moreover, microglia lacking Gal3 show enhanced TREM2 activation around plaques, a key mediator of protective microglial responses, while reducing dystrophic neurites. These findings position Gal3 as a nexus between Aβ aggregation and microglial phenotype, proposing its inhibition as a strategy to concurrently target neurotoxic inflammation in AD. Competing Interest Statement The authors have declared no competing interest.