Increased α-2,6 sialic acid on microglia in amyloid pathology is resistant to oseltamivir

Caitlyn Fastenau, Jessica L. Wickline, Sabrina Smith, Kristian F. Odfalk, Leigh Solano, Kevin F. Bieniek, Sarah C. Hopp

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Terminal sialic acid residues are present on most glycoproteins and glycolipids, but levels of sialylation are known to change in the brain throughout the lifespan as well as during disease. Sialic acids are important for numerous cellular processes including cell adhesion, neurodevelopment, and immune regulation as well as pathogen invasion into host cells. Neuraminidase enzymes, also known as sialidases, are responsible for removal of terminal sialic acids in a process known as desialylation. Neuraminidase 1 (Neu1) cleaves the α-2,6 bond of terminal sialic acids. Aging individuals with dementia are often treated with the antiviral medication oseltamivir, which is associated with induction of adverse neuropsychiatric side effects; this drug inhibits both viral and mammalian Neu1. The present study tested whether a clinically relevant antiviral dosing regimen of oseltamivir would disrupt behavior in the 5XFAD mouse model of Alzheimer’s disease amyloid pathology or wild-type littermates. While oseltamivir treatment did not impact mouse behavior or modify amyloid plaque size or morphology, a novel spatial distribution of α-2,6 sialic acid residues was discovered in 5XFAD mice that was not present in wild-type littermates. Further analyses revealed that α-2,6 sialic acid residues were not localized the amyloid plaques but instead localized to plaque-associated microglia. Notably, treatment with oseltamivir did not alter α-2,6 sialic acid distribution on plaque-associated microglia in 5XFAD mice which may be due to downregulation of Neu1 transcript levels in 5XFAD mice. Overall, this study suggests that plaque-associated microglia are highly sialylated and are resistant to change with oseltamivir, thus interfering with microglia immune recognition of and response to amyloid pathology.

Original languageEnglish (US)
Pages (from-to)1539-1555
Number of pages17
JournalGeroScience
Volume45
Issue number3
DOIs
StatePublished - Jun 2023

Keywords

  • Alzheimer’s disease
  • Aβ plaques
  • Microglia
  • Sialic acid
  • Sialylation

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine
  • Aging
  • Complementary and alternative medicine
  • veterinary (miscalleneous)

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