In Vivo Prenylomic Profiling in the Brain of a Transgenic Mouse Model of Alzheimer's Disease Reveals Increased Prenylation of a Key Set of Proteins

Dysregulation of protein prenylation has been implicated in many diseases, including Alzheimer's disease (AD). Prenylomic analysis, the combination of metabolic incorporation of an isoprenoid analogue (C15AlkOPP) into prenylated proteins with a bottom-up proteomic analysis, has allowed the identification of prenylated proteins in various cellular models. Here, transgenic AD mice were administered with C15AlkOPP through intracerebroventricular (ICV) infusion over 13 days. Using prenylomic analysis, 36 prenylated proteins were enriched in the brains of AD mice. Importantly, the prenylated forms of 15 proteins were consistently upregulated in AD mice compared to nontransgenic wild-type controls. These results highlight the power of this in vivo metabolic labeling approach to identify multiple post-translationally modified proteins that may serve as potential therapeutic targets for a disease that has proved refractory to treatment thus far. Moreover, this method should be applicable to many other types of protein modifications, significantly broadening its scope.

Automated summary

Dysregulation of protein prenylation is associated with various diseases, including Alzheimer's disease. Using a combination of metabolic labeling and proteomic analysis, 36 prenylated proteins were identified in the brains of transgenic AD mice. Importantly, the prenylated forms of 15 proteins were consistently upregulated in AD mice compared to wild-type controls. This in vivo metabolic labeling approach has the potential to identify therapeutic targets for refractory diseases and can be applied to other types of protein modifications.