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

Abstract

The {varepsilon}4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimers 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/480074v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@5865d5org.highwire.dtl.DTLVardef@185a0e0org.highwire.dtl.DTLVardef@4d2e7org.highwire.dtl.DTLVardef@b27318_HPS_FORMAT_FIGEXP M_FIG C_FIG