Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

Abstract

Alzheimer's disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this study, we analyzed transcriptomes from 2114 post-mortem brain samples from three independent cohorts and identified that the genes involved in alternative bile acid synthesis pathway was expressed in brain compared to the classical pathway. These results were supported by targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals. We reconstructed brain region-specific metabolic networks using data from three independent cohorts to assess the role of bile acid metabolism in AD pathophysiology. Our metabolic network analysis suggested that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD and cognitively normal individuals. Using the brain transcriptional regulatory network, we identified putative transcription factors regulating these metabolic genes and influencing altered metabolism in AD. Intriguingly, we find bile acids from the brain metabolomics whose synthesis cannot be explained by enzymes we find in the brain, suggesting they may originate from an external source such as the gut microbiome. These findings motivate further research into bile acid metabolism and transport in AD to elucidate their possible connection to cognitive decline.

A Machine Learning-Based Holistic Approach to Predict the Clinical Course of Patients within the Alzheimer’s Disease Spectrum1

“…Altered blood [93] and brain levels of BA [94] have been described. Interestingly, these metabolites were found to be highly relevant to drive our RF-based predictive process.…”

Revealing the Molecular Mechanisms of Alzheimer’s Disease Based on Network Analysis

“…Therefore, it is safer to assume that brain regions have different preferences for the use or production of these metabolites. Other vitamins and vitamin derivatives were mentioned for their neuroprotective effects in previous studies and interplay with fatty acids [62][63][64][65][66].…”

“…Among them, unsaturated fatty acids (especially hexanoyl-CoA and pentanoyl-CoA), retinoids and other vitamins are known to improve cognitive abilities [68][69][70][71]. Their neuroprotective effects were studied extensively and put forth clinically [64][65][66]. Thus, reintroducing them may ameliorate cognitive decline.…”

Infection and inflammation: New perspectives on Alzheimer's disease

“…Baloni et al analyzed transcriptome data from 2114 postmortem brain samples from ROSMAP, Mayo Clinic and the Mount Sinai Brain Bank. They reconstructed brain region-specific metabolic networks and found that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD patients versus healthy individuals ( Baloni et al, 2019 ). Some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, raising the possibility that they could originate from the gut microbiome and get transported into the brain ( Baloni et al, 2019 ).…”