Incorporating Mitochondrial Gene Expression Changes Within a Testable Mathematical Model for Alzheimer’s Disease: Stress Response Modulation Predicts Potential Therapeutic Targets

Abstract

Background: Alzheimer’s disease is a specific form of dementia characterized by the aggregation of amyloid-β plaques and tau tangles. New research has found that the formation of these aggregates occurs after dysregulation of cellular respiration and the production of radical oxygen species. Proteomic data shows that these changes are also related to unique gene expression patterns. Objective: This study is designed to incorporate both proteomic and gene expression data into a testable mathematical model for AD. Manipulation of this new model allows the identification of potential therapeutic targets for AD. Methods: We investigate the impact of these findings on new therapeutic targets via metabolic flux analysis of sirtuin stress response pathways while also highlighting the importance of metabolic enzyme activity in maintaining proper respiratory activity. Results: Our results indicate that protective changes in SIRT1 and AMPK expression are potential avenues for therapeutics. Conclusion: Combining our mitochondrial gene expression analyses with available protein data allowed the construction of a new mathematical model for AD that provides a useful approach to test the efficacy of potential AD therapeutic targets.