ABSTRACT: Neuroinflammation is a hallmark of Alzheimer’s disease (AD), yet the molecular mecha- nisms linking microglial dysfunction to amyloid-β (Aβ) pathology remain incompletely understood. Here, we identify galectin-3 (Gal3) as a regulator of plaque-associated microglial responses, linking Aβ aggregation, lysosomal function, and neuritic pathol- ogy. Using postmortem brain tissue from AD patients, we found that Gal3+ micro- glia preferentially associate with cored plaques and correlate with increased LAMP1+ dystrophic neurites. Gal3 was also detected in microglial lysosomal compartments, extramicroglial dystrophic structures, and in association with extracellular amyloid fibrils, suggesting roles in both intracellular and extracellular Aβ processing. In APP mice, Gal3 deficiency reduced plaque burden and neuritic dystrophy, increased plaque compaction, and enhanced TREM2 coverage around amyloid plaques. Mechanistically, in vitro microglial experiments showed that Gal3 modulates Aβ uptake and lysosomal processing, whereas lysosomal dysfunction promoted the accumulation of fibrillar Aβ from initially monomeric species, particularly in Gal3-deficient cells. Cell-free assays demonstrated that Gal3 preferentially binds fibrillar Aβ, inhibits secondary nucleation, and alters fibril morphology, while Gal3-modified fibrillar Aβ reduces N2a neuronal cell number. Finally, in silico structural analyses identified candidate Gal3 interactors enriched in leucine-rich-repeat and immunoglobulin-like proteins, supporting a role for this lectin in immune receptor regulation. Complementary in vivo transcriptomic profiling showed that Gal3 deletion suppresses type I interferon and microglial neuro- degenerative transcriptional signatures. Together, these findings position Gal3 at the interface between Aβ remodeling, lysosomal homeostasis, and plaque-associated micro- glial responses in AD.
