Galectin-3 deletion modulates microglial phenotype and Aβ response via TREM2 activation while attenuating neuroinflammation
Camprubi-Ferrer, L.; Soldan-Hidalgo, J.; Axell, E.; Garcia-Cruzado, M.; Yang, Y.; Fernandez-Calle, R.; Larlham, L.; Chouhan, B.; Garcia-Revilla, J.; Talaveron, R.; Paulus, A.; Danielson, L.; Gomez-Arboledas, A.; Klementieva, O.; Gutierrez, A.; Vitorica, J.; Boza-Serrano, A.; Frontinan, J.; Venero, J. L.; Deierborg, T.
Show abstract
Galectin-3 (Gal3) is a regulator of microglial activation implicated in Alzheimers disease (AD). However, Gal3 role in modulating microglial phenotype towards amyloid-beta (A{beta}) remains poorly understood. We demonstrate that Gal3 affects several microglial functions and binds A{beta} fibrils with high affinity, stabilizing aggregation intermediates that alter fibril kinetics and morphology. Furthermore, Gal3 deletion affects the direct relationship between microglia and A{beta}, 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 A{beta} 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 A{beta} aggregation and microglial phenotype, proposing its inhibition as a strategy to concurrently target neurotoxic inflammation in AD.
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