@article{68ba21bbd0ca4fe083fb6beb9ae569f9,
title = "Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice",
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.",
author = "Fleeman, {Rebecca M.} and Amanda Snyder and Kuhn, {Madison K.} and Chan, {Dennis C.} and Smith, {Grace C.} and Crowley, {Nicole A.} and Arnold, {Amy C.} and Proctor, {Elizabeth A.}",
note = "Funding Information: This work was supported by R01AG072513 from the National Institute on Aging (EAP), R01AA209403 from the National Institute on Alcohol Abuse and Alcoholism (NAC), and start-up funds from the Penn State College of Medicine Departments of Neurosurgery and Pharmacology (EAP). RMF is supported by NIH NRSA predoctoral fellowship F31AG071131 from the National Institute on Aging. MKK and DCC are supported by training fellowship T32NS115667 from the National Institute of Neurological Disorders and Stroke. We thank Lynne Beidler for help in mouse handling and colony management and Marianne Klinger for help in brain embedding, slicing, and sample mounting. The Metabolic Phenotyping Core (RRID:SCR_022565) services and instruments used in this project were funded, in part, by the Pennsylvania State University College of Medicine via the Office of the Vice Dean of Research and Graduate Students and the Pennsylvania Department of Health using Tobacco Settlement Funds (CURE). The content is solely the responsibility of the authors and does not necessarily represent the official views of the University or College of Medicine. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. The Core also acknowledges support from NIH through S10OD026980. Funding Information: This work was supported by R01AG072513 from the National Institute on Aging (EAP), R01AA209403 from the National Institute on Alcohol Abuse and Alcoholism (NAC), and start-up funds from the Penn State College of Medicine Departments of Neurosurgery and Pharmacology (EAP). RMF is supported by NIH NRSA predoctoral fellowship F31AG071131 from the National Institute on Aging. MKK and DCC are supported by training fellowship T32NS115667 from the National Institute of Neurological Disorders and Stroke. We thank Lynne Beidler for help in mouse handling and colony management and Marianne Klinger for help in brain embedding, slicing, and sample mounting. The Metabolic Phenotyping Core (RRID:SCR_022565) services and instruments used in this project were funded, in part, by the Pennsylvania State University College of Medicine via the Office of the Vice Dean of Research and Graduate Students and the Pennsylvania Department of Health using Tobacco Settlement Funds (CURE). The content is solely the responsibility of the authors and does not necessarily represent the official views of the University or College of Medicine. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. The Core also acknowledges support from NIH through S10OD026980. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2023",
month = mar,
doi = "10.1016/j.neurobiolaging.2022.11.015",
language = "English (US)",
volume = "123",
pages = "154--169",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",
}