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

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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.

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Data Availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

Abbreviations

Neu1:

neuraminidase 1

AD:

Alzheimer’s Disease

5XFAD:

Five familiar Alzheimer’s disease mutations

Aβ:

amyloid beta

PTM:

post-translational modification

SA:

sialic acid

Siglec:

sialic acid binding immunoglobulin-like lectin

CSF:

cerebral spinal fluid

MCI:

mild cognitive impairment

MS:

mass spectrometry

APP:

amyloid precursor protein

WT:

wild-type

PCR:

polymerase chain reaction

OF:

open field

NOR:

novel object recognition

DI:

discrimination index

IHC:

immunohistochemistry

IF:

immunofluorescence

ROI:

region of interest

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Acknowledgements

The authors would like to thank Mallory Maybrier for histological expertise and Kathleen Bensen for cell counting.

Funding

This work was supported by The National Institutes of Health [T32AG021890 to CF, NS082145 to KFB, R21AG072423 and pilot funding under P30AG013319 to SCH, and P30AG066546 to KFB], the Texas Alzheimer’s Research and Care Consortium to KFB, and the Bartell and Mollie Zachry Endowment for Alzheimer’s Research and Patient Care to KFB.

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  1. Department of Pharmacology, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Caitlyn Fastenau, Jessica L. Wickline, Sabrina Smith, Kristian F. Odfalk & Sarah C. Hopp

  2. Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio, TX, USA

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

  3. Department of Pathology and Laboratory Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX, USA

    Kevin F. Bieniek

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Fastenau, C., Wickline, J.L., Smith, S. et al. Increased α-2,6 sialic acid on microglia in amyloid pathology is resistant to oseltamivir. GeroScience 45, 1539–1555 (2023). https://doi.org/10.1007/s11357-023-00761-1

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