Dataset Information

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

ABSTRACT: 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 AppNL-G-F. 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 AppNL-G-F 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.

SUBMITTER: Kaur H

PROVIDER: S-EPMC8303891 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Kaur Harpreet H Seeger Drew D Golovko Svetlana S Golovko Mikhail M Combs Colin Kelly CK

International journal of molecular sciences 20210712 14

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 ...[more]

PMID: 34299071

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Project description:BackgroundAlzheimer's disease (AD) is the most common cause of dementia. Effective therapy, early diagnosis, and intervention are still lacking. Non-drug therapy and lifestyle interventions have become important means to prevent the occurrence and progression of AD, with nutritional therapy being one such example. Nutritional therapy, as a non-pharmacological intervention for AD, has made significant progress and shown significant promise for the development of treatment regimens in recent years. Niacin is a critical vitamin available in the forms of nicotinamide (NAM) and nicotinic acid (NA). In tissues, niacin is transformed into nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are involved in a variety of cellular processes. Recent researches indicate that niacin may be beneficial in the prevention and treatment of aging, cancer, and metabolic illnesses.MethodsTo detect the mechanism of affection of niacin in AD, we found out GSE135999 from the Gene Expression Omnibus (GEO) database which is microarray data containing samples of 24 wild-type (WT) and 24 APP/PS1 AD mice, given either nicotinamide riboside (NR; 12 mM) or nothing (CTR) in their drinking water. We conducted a more reliable data analysis method Weighted Gene Co-expression Network Analysis (WGCNA) to confirm the central players (hub genes) and related pathways associated between niacin and AD. To validate the affection of niacin in AD mice, we selected 6 WT and 12 APP/PS1 transgenic mice, the 12 APP/PS1 mice were treated with a niacin acid supplement diet or normal food. Six months later, behavioral tests were performed.ResultsOur research revealed the hub genes and pathways involved in the enhancement of cognition in AD animal models with niacin supplementation, through transcriptomics analysis, systems biology technique and in vivo. The hub genes were Ctnnb1, Mdm2, Crebbp, Gnb2l1/RACK1 and Pten. The related pathways were circadian rhythm, ubiquitin-mediated proteolysis, and long-term potentiation.ConclusionsA niacin supplementary diet may be a safe and simple choice for AD prevention and treatment. Niacin can enhance cognitive capacity in AD through a variety of mechanisms, among which Ctnnb1, Mdm2, Crebbp, Gnb2l1/RACK1 and Pten are significant.

Dataset Information

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

Publications

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

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