title: Integrating transcriptomics with metabolic modeling predicts biomarkers and drug targets for Alzheimer's disease.
abstract: Accumulating evidence links numerous abnormalities in cerebral metabolism with the progression of Alzheimer's disease (AD), beginning in its early stages. Here, we integrate transcriptomic data from AD patients with a genome-scale computational human metabolic model to characterize the altered metabolism in AD, and employ state-of-the-art metabolic modelling methods to predict metabolic biomarkers and drug targets in AD. The metabolic descriptions derived are first tested and validated on a large scale versus existing AD proteomics and metabolomics data. Our analysis shows a significant decrease in the activity of several key metabolic pathways, including the carnitine shuttle, folate metabolism and mitochondrial transport. We predict several metabolic biomarkers of AD progression in the blood and the CSF, including succinate and prostaglandin D2. Vitamin D and steroid metabolism pathways are enriched with predicted drug targets that could mitigate the metabolic alterations observed. Taken together, this study provides the first network wide view of the metabolic alterations associated with AD progression. Most importantly, it offers a cohort of new metabolic leads for the diagnosis of AD and its treatment.
authors.affiliation: The Sackler School of Medicine - Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shiri
authors.initials: S
authors.lastname: Stempler
authors.affiliation: The Blavatnik School of Computer Science - Tel Aviv University, Tel Aviv, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Yizhak
authors.affiliation: The Sackler School of Medicine - Tel Aviv University, Tel Aviv, Israel; The Blavatnik School of Computer Science - Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D053858:Metabolic Networks and Pathways; D059467:Transcriptome
chemical_list: D015415:Biomarkers