Increased Sialylation in Alzheimer’s Disease Models

Abstract

AbstractBackgroundResearch shows evidence of increased sialylation localized to pathological protein aggregates in AD autopsied brains. Sialylation is a type of glycosylation with linkage bonds of sialic acid (SA) residues on glycoproteins and glycolipids. It is unclear how changes in SA distribution in AD contributes to disease. Microglia are partially regulated by sialylation. We hypothesize decreased removal of SA residues on microglia leads to increased sialylation near amyloid‐β (Aβ) plaques, reducing microglia mediated plaque clearance.MethodA plant‐derived lectin was used to recognize α2‐6 SA bonds. Aβ plaques, microglia, and α2‐6 SA were histologically labelled in cortical brain tissue from human AD cases and 5XFAD mouse model of Aβ pathology. Stained hemibrains were imaged with confocal microscopy and quantified. To investigate the effects of reducing SA cleavage, we treated a subset of our 5XFAD and wild‐type (WT) mice with oseltamivir (Tamiflu), an inhibitor of desialylation, for five days. On day 3 and immediately following treatment, we measured cognitive and non‐cognitive behaviors using open field and novel object recognition tests.ResultQualitatively, α2‐6 SA levels displayed similar microglial‐like phenotype in 5XFAD and human AD cortical brain tissue. Two‐way ANOVA of histologically labeled hemibrains revealed 5XFAD mice had significantly increased α2‐6 SA levels compared to WT mice (p = 0.0007). High magnification image analysis supported a significant increase of α2‐6 SA area in 5XFAD mice versus WT (p<0.0001), yet there was no effect of oseltamivir treatment. Behavioral data similarly demonstrated no effect of treatment. Post‐hoc analysis of open field revealed 5XFAD mice exhibited greater velocity compared to WT (p = 0.03) and 5XFAD mice lacked habituation behavior with no decrease in velocity compared to WT (p = 0.02). Investigation of Aβ pathology indicated no oseltamivir effect.ConclusionWe observed a significant increase in α2‐6 SA in 5XFAD mice similar to human AD, suggesting a plaque associated increase in sialylation. Next, we will closely examine localization of SA in the plaque microenvironment to understand the role of sialylation in microglial interactions with disease pathology. We postulate SA residues are localized to microglia interacting with Aβ plaques, potentially aggravating pathology.