Liver Bile Acid Changes in Mouse Models of Alzheimer's Disease

• Published in: International journal of molecular sciences Vol. 22; no. 14; p. 7451
• Main Authors: Kaur, Harpreet, Seeger, Drew, Golovko, Svetlana, Golovko, Mikhail, Combs, Colin Kelly
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.07.2021; MDPI
• Subjects: Acids; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Amyloid beta-Protein Precursor - physiology; Amyloid precursor protein; Amyloidosis; Animal cognition; Animal models; Animals; Bile; bile acid; Bile acids; Bile Acids and Salts - metabolism; Cholesterol; Chromatography; Cytochrome; cytochrome P450; Disease Models, Animal; Enzymes; Female; Females; Gender aspects; Gender differences; Intermediates; Lipid metabolism; Liver; Liver - metabolism; Male; Males; Mass spectrometry; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Pathophysiology; Presenilin 1; Presenilin-1 - physiology; Proteins; Rodents; Scientific imaging; sex difference; Sex differences; Tau protein; cholesterol; cytochrome P450; Alzheimer’s disease; sex difference; bile acid
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22147451

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and . Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.