In situ spatial glycomic imaging of mouse and human Alzheimer's disease brains

Tara R. Hawkinson, Harrison A. Clarke, Lyndsay E.A. Young, Lindsey R. Conroy, Kia H. Markussen, Kayla M. Kerch, Lance Johnson, Peter T. Nelson, Chi Wang, Derek B. Allison, Matthew S. Gentry, Ramon Sun

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

N-linked protein glycosylation in the brain is an understudied facet of glucose utilization that impacts a myriad of cellular processes including resting membrane potential, axon firing, and synaptic vesicle trafficking. Currently, a spatial map of N-linked glycans within the normal and Alzheimer's disease (AD) human brain does not exist. A comprehensive analysis of the spatial N-linked glycome would improve our understanding of brain energy metabolism, linking metabolism to signaling events perturbed during AD progression, and could illuminate new therapeutic strategies. Herein we report an optimized in situ workflow for enzyme-assisted, matrix-assisted laser desorption and ionization (MALDI) mass spectrometry imaging (MSI) of brain N-linked glycans. Using this workflow, we spatially interrogated N-linked glycan heterogeneity in both mouse and human AD brains and their respective age-matched controls. We identified robust regional-specific N-linked glycan changes associated with AD in mice and humans. These data suggest that N-linked glycan dysregulation could be an underpinning of AD pathologies.

Original languageEnglish
Pages (from-to)1721-1735
Number of pages15
JournalAlzheimer's and Dementia
Volume18
Issue number10
DOIs
StatePublished - Oct 2022

Bibliographical note

Funding Information:
We would like to thank Dr. Vander Kooi and Gentry lab members for vigorous discussions regarding the work and Mrs. Dana Napier for performing immunohistochemical‐staining on tissue slices at the Markey Cancer Center. This study was supported by the National Institutes of Health (NIH) grants R35 NS116824 and P01 NS097197 awarded to Matthew S. Gentry. NIH grant R01 AG066653, St Baldrick's Career Development Award, V‐Scholar Grant, Rally Foundation Independent Investigator Grant awarded to Ramon C. Sun. Lindsey R. Conroy was supported by NIH/NCI training grant T32CA165990. This research was also supported by funding from the University of Kentucky Markey Cancer Center and the NIH‐funded Biospecimen Procurement & Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center P30CA177558.

Publisher Copyright:
© 2021 the Alzheimer's Association.

Keywords

  • MALDI imaging
  • N-linked glycosylation
  • bioenergetics
  • carbohydrate metabolism
  • neuronal function
  • synaptic transmission

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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