Protective role of Galectin-3 in prion disease through regulation of microglial PrPSc uptake.
- 1Department of Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
- 2Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland, USA.
Abstract
Microglia constitute a major innate defense mechanism against prion infection; however, the molecular pathways regulating microglial responses during disease progression remain incompletely understood. Galectin-3 (Gal3), a β-galactoside-binding lectin associated with reactive microglia in multiple neurodegenerative disorders, has been implicated in phagocytosis, inflammatory signaling, and lysosomal homeostasis. Here, we investigated the role of Gal3 in prion disease pathogenesis using prion-infected mice. Gal3 expression was undetectable in healthy brain but became upregulated beginning at late preclinical stages, increasing with disease progression. Gal3 localized predominantly to a subpopulation of reactive IBA1-positive microglia, particularly within the thalamus, and inversely correlated with expression of the homeostatic microglial markers P2Y12 and TMEM119, consistent with acquisition of a reactive phenotype. Microglia engaged in neuronal envelopment displayed elevated Gal3 expression during terminal disease. Constitutive deletion of Gal3 significantly accelerated clinical disease progression without altering total PrPSc accumulation, reactive gliosis, neuronal envelopment, or overall microglial and astrocytic activation. However, Gal3 deficiency markedly reduced microglial uptake of PrPSc, resulting in a lower intracellular-to-extracellular PrPSc ratio, supporting a role for Gal3 in phagocytic sequestration of prions. In contrast, Gal3 deficiency did not impair lysosomal activity, lysosomal membrane integrity, or expression of genes involved in lysosomal repair pathways. Likewise, selective inhibition of autophagy in myeloid cells exerted only minor effects on disease progression. Collectively, these findings identify Gal3 as a sensitive marker of reactive microglia that contributes to microglial uptake of PrPSc and exerts a protective role during prion disease progression.
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BibTeX
@article{makarava2026protective,
title = {{Protective role of Galectin-3 in prion disease through regulation of microglial PrPSc uptake.}},
author = {Natallia Makarava and Tarek Safadi and Narayan P Pandit and Olga Mychko and Olga Bocharova and Alexey Shevelkin and Kara Molesworth and Marta M Lipinski and Ilia V Baskakov},
journal = {Brain pathology (Zurich, Switzerland)},
year = {2026},
month = oct,
doi = {10.1111/bpa.70161},
url = {https://europepmc.org/article/MED/42914142},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Protective role of Galectin-3 in prion disease through regulation of microglial PrPSc uptake.
AU - Natallia Makarava
AU - Tarek Safadi
AU - Narayan P Pandit
AU - Olga Mychko
AU - Olga Bocharova
AU - Alexey Shevelkin
AU - Kara Molesworth
AU - Marta M Lipinski
AU - Ilia V Baskakov
PY - 2026
DA - 2026/10/22
JO - Brain pathology (Zurich, Switzerland)
DO - 10.1111/bpa.70161
UR - https://europepmc.org/article/MED/42914142
AB - Microglia constitute a major innate defense mechanism against prion infection; however, the molecular pathways regulating microglial responses during disease progression remain incompletely understood. Galectin-3 (Gal3), a β-galactoside-binding lectin associated with reactive microglia in multiple neurodegenerative disorders, has been implicated in phagocytosis, inflammatory signaling, and lysosomal homeostasis. Here, we investigated the role of Gal3 in prion disease pathogenesis using prion-infected mice. Gal3 expression was undetectable in healthy brain but became upregulated beginning at late preclinical stages, increasing with disease progression. Gal3 localized predominantly to a subpopulation of reactive IBA1-positive microglia, particularly within the thalamus, and inversely correlated with expression of the homeostatic microglial markers P2Y12 and TMEM119, consistent with acquisition of a reactive phenotype. Microglia engaged in neuronal envelopment displayed elevated Gal3 expression during terminal disease. Constitutive deletion of Gal3 significantly accelerated clinical disease progression without altering total PrPSc accumulation, reactive gliosis, neuronal envelopment, or overall microglial and astrocytic activation. However, Gal3 deficiency markedly reduced microglial uptake of PrPSc, resulting in a lower intracellular-to-extracellular PrPSc ratio, supporting a role for Gal3 in phagocytic sequestration of prions. In contrast, Gal3 deficiency did not impair lysosomal activity, lysosomal membrane integrity, or expression of genes involved in lysosomal repair pathways. Likewise, selective inhibition of autophagy in myeloid cells exerted only minor effects on disease progression. Collectively, these findings identify Gal3 as a sensitive marker of reactive microglia that contributes to microglial uptake of PrPSc and exerts a protective role during prion disease progression.
SN - 1015-6305
SN - 1750-3639
ER -