Proteomic and metabolic profiling reveals APOE4-dependent shifts in whole brain, neuronal, and astrocytic mitochondrial function and glycolysis

Lysaker, C. R.; Johnson, C.; Csikos, V.; Franczak, E.; Benson, M.; Gilmore, C.; Birky, C.; Davis, X.; McCoin, C.; Smith, K.; Puchalska, P.; Crawford, P.; Slawson, C.; Thyfault, J.; Geiger, P.; Morris, J.; Wilkins, H. M.

doi:10.1101/2025.06.15.659811

bioRxiv · 10.1101/2025.06.15.659811

Proteomic and metabolic profiling reveals APOE4-dependent shifts in whole brain, neuronal, and astrocytic mitochondrial function and glycolysis

Lysaker, C. R.·Johnson, C.·Csikos, V.·Franczak, E.·Benson, M.·Gilmore, C.·Birky, C.·Davis, X.·McCoin, C.·Smith, K.·Puchalska, P.·Crawford, P.·Slawson, C.·Thyfault, J.·Geiger, P.·Morris, J.·Wilkins, H. M.

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Abstract

Apolipoprotein E (APOE) genetic variation is the strongest genetic risk factor for late onset Alzheimers disease (LOAD). Studies on APOE genotype dependent changes have largely focused on amyloid beta (A{beta}) aggregation, disease pathology, and lipid metabolism. Recently, there has been increased interest in the relationship between metabolic function and APOE genetic variation. In this study, we examined how APOE genotype can alter metabolism in the brains of young male and female APOE3 and APOE4 targeted replacement (TR) mice. In combination with this, we also examined cell type-specific differences using induced pluripotent stem cell (iPSC) derived astrocytes and neurons. We found sex and genotype dependent changes to metabolism in the brains of young APOE TR mice. Specifically, APOE4 mice show signs of metabolic stress and compensatory mechanisms in the brain. Using proteomics and stable isotope tracing metabolomics, we found that APOE4 iAstrocytes and iNeurons exhibit signs of inflammation, mitochondrial dysfunction, altered TCA cycle and malate-aspartate shuttle activity, and a metabolic shift toward glycolysis. Taken together, this data indicates APOE4 causes early changes to metabolism within the central nervous system. While this study establishes a relationship between APOE genotype and alterations in bioenergetics, additional studies are needed to investigate underlying mechanisms.

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Lysaker, C. R., Johnson, C., Csikos, V., Franczak, E., Benson, M., Gilmore, C., Birky, C., Davis, X., McCoin, C., Smith, K., Puchalska, P., Crawford, P., Slawson, C., Thyfault, J., Geiger, P., Morris, J., Wilkins, H. M.. 2025-06-16. Proteomic and metabolic profiling reveals APOE4-dependent shifts in whole brain, neuronal, and astrocytic mitochondrial function and glycolysis. https://doi.org/10.1101/2025.06.15.659811

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