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

Rebecca M Fleeman; Amanda M Snyder; Madison K Kuhn; Dennis C Chan; Grace C Smith; Nicole A Crowley; Amy C Arnold; Elizabeth A Proctor

doi:10.1016/j.neurobiolaging.2022.11.015

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

Neurobiol Aging. 2023 Mar:123:154-169. doi: 10.1016/j.neurobiolaging.2022.11.015. Epub 2022 Dec 5.

Authors

Rebecca M Fleeman¹, Amanda M Snyder², Madison K Kuhn³, Dennis C Chan³, Grace C Smith⁴, Nicole A Crowley⁵, Amy C Arnold⁶, Elizabeth A Proctor⁷

Affiliations

¹ Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, USA; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA.
² Department of Neurology, Penn State College of Medicine, Hershey, PA, USA.
³ Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, USA; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, USA; Center for Neural Engineering, Pennsylvania State University, University Park, PA, USA.
⁴ Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, USA; Department of Biology, Pennsylvania State University, University Park, PA, USA.
⁵ Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, USA; Center for Neural Engineering, Pennsylvania State University, University Park, PA, USA; Department of Biology, Pennsylvania State University, University Park, PA, USA.
⁶ Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA.
⁷ Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, USA; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA; Department of Biomedical Engineering, Pennsylvania State University, University Park, PA, USA; Center for Neural Engineering, Pennsylvania State University, University Park, PA, USA; Department of Engineering Science & Mechanics, Pennsylvania State University, University Park, PA, USA. Electronic address: eproctor@psu.edu.

PMID: 36572594
PMCID: PMC9892258
DOI: 10.1016/j.neurobiolaging.2022.11.015

Abstract

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.

Keywords: APOE; Alzheimer's disease; Cytokines; Inflammation; Metabolism.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / metabolism
Animals
Apolipoprotein E2 / genetics
Apolipoprotein E3 / genetics
Apolipoprotein E4* / genetics
Apolipoprotein E4* / metabolism
Apolipoproteins E / genetics
Brain / metabolism
Cytokines / metabolism
Female
Genotype
Male
Mice

Substances

Apolipoprotein E4
Cytokines
Apolipoproteins E
Apolipoprotein E3
Apolipoprotein E2

Abstract

Publication types

MeSH terms

Substances

Grants and funding