Quantitative and Kinetic Proteomics Reveal ApoE Isoform-dependent Proteostasis Adaptations in Mouse Brain

by Nathan R. Zuniga, Noah E. Earls, Ariel E. A. Denos, Jared M. Elison, Benjamin S. Jones, Ethan G. Smith, Noah G. Moran, Katie L. Broce, Gerome M. Romero, Chad D. Hyer, Kimberly B. Wagstaff, Haifa M. Almughamsi, Mark K. Transtrum, John C. Price

Apolipoprotein E (ApoE) polymorphisms modify the risk of Alzheimer’s disease with ApoE4 strongly increasing and ApoE2 modestly decreasing risk relative to the control ApoE3. To investigate how ApoE isoforms alter risk, we measured changes in proteome homeostasis in transgenic mice expressing a human ApoE gene (isoform 2, 3, or 4). The regulation of each protein’s homeostasis is observed by measuring turnover rate and abundance for that protein. We identified 4849 proteins and tested for ApoE isoform-dependent changes in the homeostatic regulation of ~2700 ontologies. In the brain, we found that ApoE4 and ApoE2 both lead to modified regulation of mitochondrial membrane proteins relative to the wild-type control ApoE3. In ApoE4 mice, lack of cohesion between mitochondrial membrane and matrix proteins suggests that dysregulation of proteasome and autophagy is reducing protein quality. In ApoE2, proteins of the mitochondrial matrix and the membrane, including oxidative phosphorylation complexes, had a similar increase in degradation which suggests coordinated replacement of the entire organelle. In the liver we did not observe these changes suggesting that the ApoE-effect on proteostasis is amplified in the brain relative to other tissues. Our findings underscore the utility of combining protein abundance and turnover rates to decipher proteome regulatory mechanisms and their potential role in biology.