Anti-Alpha-Gal Antibodies Against Gangliosides: Preliminary Data on a New Autoimmune Target in Alzheimer's Disease...

Human anti-αGal antibodies (Abs), known for their marked polyreactivity, have been detected bound to the gray matter of the brains of Alzheimer's disease (AD) patients, although their targets were unclear. Since αGal is a strictly xenogenic antigen absent in humans, this observation raised questions regarding the nature of the structures recognized by these antibodies. In this study, we investigated their potential interaction with gangliosides-glycan structures that are highly abundant in the central nervous system. Using a competitive inhibition ELISA, serum profiles of anti-αGal Abs isotypes and their indirect cross-reactivity with selected soluble gangliosides were analyzed in AD patients and healthy subjects (HSs). AD patients showed reduced levels of anti-αGal IgG and IgM, but increased IgA compared to HSs. Notably, pre-incubation with GM1, GM2, or GD1b did not reduce αGal-HSA binding in HS sera. In contrast, in AD sera, pre-incubation with GD1b reduced residual αGal-HSA binding for all antibody isotypes; additionally, GM1 inhibited IgM binding, and GM2 inhibited IgA binding. These results should therefore be interpreted as competitive inhibition patterns consistent with ganglioside-associated cross-reactivity rather than as direct evidence of antibody binding to immobilized gangliosides. Overall, the findings provide preliminary evidence that, in AD sera, a fraction of αGal-HSA-reactive antibodies can be competitively inhibited by selected gangliosides. This observation supports the presence of an altered humoral anti-carbohydrate signature in AD and identifies neuronal gangliosides as plausible candidate autologous targets that may help explain the previously reported binding of anti-αGal Abs to gray matter. However, given the indirect nature of the assay, these data should be considered hypothesis-generating and require confirmation by direct binding approaches.