Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice

The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines, and these signatures are APOE genotype dependent. Ours is the first study to identify a quantitative and predictive link between systemic metabolism and specific pathological cytokine signatures in the brain. Our results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery.

© This manuscript version is made available under the CC-BY-NC-ND 4.0 license



Work Title Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice
Open Access
  1. Rebecca M. Fleeman
  2. Amanda M. Snyder
  3. Madison K. Kuhn
  4. Dennis C. Chan
  5. Grace C. Smith
  6. Nicole A. Crowley
  7. Amy C. Arnold
  8. Elizabeth A. Proctor
  1. APOE
  2. Inflammation
  3. Metabolism
  4. Alzheimer's disease
  5. Cytokines
License CC BY-NC-ND 4.0 (Attribution-NonCommercial-NoDerivatives)
Work Type Article
  1. Neurobiology of Aging
Publication Date January 25, 2023
Publisher Identifier (DOI)
Deposited July 27, 2023




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Work History

Version 1

  • Created
  • Added fskcscap-NeurobiolAging23-acceptedVersion.pdf
  • Added Creator Rebecca M Fleeman
  • Added Creator A Marie Snyder
  • Added Creator M K Kuhn
  • Added Creator D C Chan
  • Added Creator G C Smith
  • Added Creator Nicole Crowley
  • Added Creator Amy Christine Arnold
  • Added Creator Elizabeth Anne Proctor
  • Published
  • Updated Keyword, Publication Date Show Changes
    • APOE, Inflammation, Metabolism, Alzheimer's disease, Cytokines
    Publication Date
    • 2023-03-01
    • 2023-01-25
  • Renamed Creator Rebecca M. Fleeman Show Changes
    • Rebecca M Fleeman
    • Rebecca M. Fleeman
  • Renamed Creator Amanda M. Snyder Show Changes
    • A Marie Snyder
    • Amanda M. Snyder
  • Renamed Creator Madison K. Kuhn Show Changes
    • M K Kuhn
    • Madison K. Kuhn
  • Renamed Creator Dennis C. Chan Show Changes
    • D C Chan
    • Dennis C. Chan
  • Renamed Creator Grace C. Smith Show Changes
    • G C Smith
    • Grace C. Smith
  • Renamed Creator Nicole A. Crowley Show Changes
    • Nicole Crowley
    • Nicole A. Crowley
  • Renamed Creator Amy C. Arnold Show Changes
    • Amy Christine Arnold
    • Amy C. Arnold
  • Renamed Creator Elizabeth A. Proctor Show Changes
    • Elizabeth Anne Proctor
    • Elizabeth A. Proctor
  • Updated