Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer's Disease

Abstract

Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline.

Keywords: Alzheimer's disease; bile acids; cholesterol metabolism; genome-scale metabolic models; metabolomics; transcriptional regulatory networks; transcriptomics.

Graphical abstract

Figure 1

Graphical Overview of Analyses Described Herein to Study Altered Cholesterol and Bile Acid (BA) Metabolism in AD Numbers of samples from each brain region are indicated along with AD and control samples and male/female breakdown in parentheses. We used the post-mortem brain sample transcriptome data to generate region-specific metabolic networks. We used these networks to study BA and cholesterol metabolism. Using the brain transcriptional regulatory network, we identified transcription factors that regulate genes in cholesterol and BA metabolism. See also Table S1.

Figure 2

Transcriptomic Analysis of Genes Associated with Cholesterol and BA Metabolism Heatmap of cholesterol (A) and BA metabolism (B) genes. The color gradient is based on ubiquity scores calculated for the genes and the gray color represents genes having no expression data in the brain regions from the 3 cohorts. Brain regions represented in the plot are cerebellum (CER), prefrontal cortex (FC), temporal cortex (TC), frontal pole (FP), inferior frontal gyrus (IFG), parahippocampal gyrus (PHG), and superior temporal gyrus (STG). The function of genes is indicated on the left side of each heatmap.

Figure 3

Schematic Representation of BA Synthesis Pathway in Humans Genes expressed in brain samples from our analysis are highlighted in pink. The order of enzymatic reactions can vary. Based on the results from MahmoudianDehkordi et al., BAs have been marked as neuroprotective or cytotoxic.

Figure 4

Metabolomics Analysis of Post-mortem Brain Samples to Identify Levels of Primary and Secondary BAs Bar plots representing the ratio of BAs with respect to cholic acid (CA) (primary BA) are shown here. The primary and secondary BAs measured from 111 brain samples from the ROSMAP study are represented here. The blue bars represent AD samples and the light orange bars represent control samples. See also Table S3.

Figure 5

Metabolic Reconstruction of Brain Regions and Analysis of Reactions Involved in BA Metabolism Clustergram for 518 reactions involved in BA metabolism. (A) Mayo clinic cohort (CER and TC). (B) ROSMAP cohort (FC). (C) Mount Sinai Brain Bank (FP, IFG, STG, and PHG). The rows correspond to BA reactions in the network and the columns are colored based on the brain regions.

Figure 6

Transcriptional Regulators Responsible for Altered Cholesterol and BA Metabolism in AD Transcriptional regulatory network of brain highlighting transcription factors (TFs) and metabolic genes involved in cholesterol and BA metabolism. TFs are represented as blue triangles, BA metabolism genes as yellow circles, and cholesterol metabolism genes as pink rectangles. The significant genes are highlighted with a red border and TFs in a darker shade of blue. The red edges represent interactions between genes and TFs.