Understanding the Role of Bile Acids in Alzheimer?s Disease

Alzheimer’s disease (AD) is the leading cause of dementia. AD-related neurodegeneration has been correlated with metabolic dysfunction. An integrative analysis of transcriptomic, proteomic and metabolomic data from the brains of post-mortem AD patients and controls has provided evidence of genes and metabolites involved in altered metabolic pathways in AD. We have built context-specific draft metabolic networks for multiple brain regions, using high throughput transcriptome data of post-mortem brain samples from AD patients and controls, and integrated them with Recon3D, the most comprehensive and recent human metabolic reconstruction. We previously identified a role for circulating bile acids in AD, as well as upstream changes in cholesterol metabolism. Primary bile acids are synthesized in the liver, whereas secondary bile acids are typically produced by bacteria in the gut. Increased levels of secondary bile acids and ratios to their primary bile acid educts have been linked to AD and cognitive decline. Expression analysis shows that genes involved in alternative bile acid synthesis pathways are expressed in the brain, while genes in the classical pathway are not, thus providing insights into bile acid metabolism in the brain. By integrating transcriptomics data and metabolomics measurements of bile acids from brain tissue of AD patients and controls within these metabolic networks, our models can capture in silico changes in these pathways, highlighting the role of brain bile acid metabolism in AD pathophysiology. Our brain-tissue metabolic models can be exploited to capture in silico changes and possibly identify metabolic biomarkers prior to disease manifestation, making them useful for identifying at-risk individuals. Using the information of brain-specific transcriptional regulatory networks, we aim to identify key genes involved in regulating metabolic changes. Our approach combines multi-omics information and provides insights into interactions of primary and secondary bile acids and their possible connection to cognitive decline and AD.