Lectins and neurodegeneration: A glycobiologist's perspective

Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, affect an increasing number of people in aging societies, dramatically reducing the quality of life of those affected. Hence, intensive research efforts are aimed at understanding the molecular mechanisms of the disease progress, with the hope for developing effective therapeutic strategies. The progress of neurodegenerative diseases is associated with a complex activity of the immune system in the brain tissue. Carbohydrate-binding proteins (lectins) play a key role in the inflammation-related activation of microglia. Siglecs, maintained in an active state by binding to sialic acid-terminated glycoconjugates, help establish homeostasis by protecting nerve cells from phagocytosis and preventing triggering receptor expressed on myeloid cells 2 (TREM2) activation. Upon activation, microglia release sialidase, an enzyme that cleaves sialic acid residues from glycoconjugates, thereby exposing galactose as the next monosaccharide in the glycan chain. After losing siglec-mediated protection, the glycan becomes a ligand for Galectin-3 (Gal-3). Overexpression of this lectin under inflammatory conditions activates TREM2 and TLR4 signaling pathways, enhances the phagocytic activity of microglia and leads to tissue damage. Blocking Gal-3 interactions with the thiodigalactoside inhibitor (TD-139) appears to be a promising novel approach to pharmacologically alleviating neuroinflammation.