Tissue-Specific Metabolomics Analysis Identifies the Liver as a Major Organ of Metabolic Disorders in Amyloid Precursor Protein/Presenilin 1 Mice of Alzheimer’s Disease

Zheng, Hong; Cai, Aimin; Shu, Qi; Niu, Yan; Xu, Pengfei; Li, Chen; Lin, Li; Gao, Hongchang

doi:10.1021/acs.jproteome.8b00847

Cited by 25 publications

(24 citation statements)

References 46 publications

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“…1). In addition, recent tissue-specific metabolomic analysis revealed that the liver was the earliest affected organ in A␤PP/PS1 mice during amyloid pathology progression [14]. Genetic variants affecting A␤PP and A␤ processing are associated not only with early-onset autosomal dominant AD but also with LOAD [15].…”

Section: Productionmentioning

confidence: 99%

Is Alzheimer’s Disease a Liver Disease of the Brain?

Bassendine

Taylor-Robinson

Fertleman

et al. 2020

JAD

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Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer's disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-␤ (A␤) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. A␤ generation is a normal physiological process; the steady-state level of A␤ in the brain is determined by balance between A␤ production and its clearance. We present evidence suggesting that the liver is the origin of brain A␤ deposits and that it is involved in peripheral clearance of circulating A␤ in the blood. Hence the liver could be targeted to decrease A␤ production or increase peripheral clearance.

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Section: Productionmentioning

confidence: 99%

Is Alzheimer’s Disease a Liver Disease of the Brain?

Bassendine

Taylor-Robinson

Fertleman

et al. 2020

JAD

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“…The EGFR signalling network has been identified as a key player in liver disease [ 39 ]. The precise function of APP is unknown but it is involved in Alzheimer’s disease and also has been hypothesised to be involved in liver metabolism [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Functional module detection through integration of single-cell RNA sequencing data with protein–protein interaction networks

et al. 2020

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Background Recent advances in single-cell RNA sequencing have allowed researchers to explore transcriptional function at a cellular level. In particular, single-cell RNA sequencing reveals that there exist clusters of cells with similar gene expression profiles, representing different transcriptional states. Results In this study, we present scPPIN, a method for integrating single-cell RNA sequencing data with protein–protein interaction networks that detects active modules in cells of different transcriptional states. We achieve this by clustering RNA-sequencing data, identifying differentially expressed genes, constructing node-weighted protein–protein interaction networks, and finding the maximum-weight connected subgraphs with an exact Steiner-tree approach. As case studies, we investigate two RNA-sequencing data sets from human liver spheroids and human adipose tissue, respectively. With scPPIN we expand the output of differential expressed genes analysis with information from protein interactions. We find that different transcriptional states have different subnetworks of the protein–protein interaction networks significantly enriched which represent biological pathways. In these pathways, scPPIN identifies proteins that are not differentially expressed but have a crucial biological function (e.g., as receptors) and therefore reveals biology beyond a standard differential expressed gene analysis. Conclusions The introduced scPPIN method can be used to systematically analyse differentially expressed genes in single-cell RNA sequencing data by integrating it with protein interaction data. The detected modules that characterise each cluster help to identify and hypothesise a biological function associated to those cells. Our analysis suggests the participation of unexpected proteins in these pathways that are undetectable from the single-cell RNA sequencing data alone. The techniques described here are applicable to other organisms and tissues.

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“…It is known, from AD models in rodents, that AD impairs the function of peripheral organs such as liver, kidney, and small intestine (González-Domínguez et al 2015b ; Pan et al 2019 ). Metabolomic results from APP/PS1 mouse models revealed that the liver was the organ first affected during the progression of amyloid pathology, demonstrating impaired energy metabolism, amino acid metabolism, nucleic acid metabolism, as well as ketone and fatty acid metabolism (Zheng et al 2019 ). In addition the systemic effects of physical exercise have also been well demonstrated (Radak et al 2008 , 2019 , 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Exercise combined with a probiotics treatment alters the microbiome, but moderately affects signalling pathways in the liver of male APP/PS1 transgenic mice

et al. 2020

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It has been demonstrated that physical exercise and probiotic supplementation delay the progress of Alzheimer’s Disease (AD) in male APP/PS1TG mice. However, it has also been suggested that both exercise and AD have systemic effects. We have studied the effects of exercise training and probiotic treatment on microbiome and biochemical signalling proteins in the liver. The results suggest that liver is under oxidative stress, since SOD2 levels of APP/PS1 mice were decreased when compared to a wild type of mice. Exercise training prevented this decrease. We did not find significant changes in COX4, SIRT3, PGC-1a or GLUT4 levels, while the changes in pAMPK/AMPK, pmTOR/mTOR, pS6/S6 and NRF2 levels were randomly modulated. The data suggest that exercise and probiotics-induced changes in microbiome do not strongly affect mitochondrial density or protein synthesis-related AMPK/mTOR/S6 pathways in the liver of these animals.

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Tissue-Specific Metabolomics Analysis Identifies the Liver as a Major Organ of Metabolic Disorders in Amyloid Precursor Protein/Presenilin 1 Mice of Alzheimer’s Disease

Cited by 25 publications

References 46 publications

Is Alzheimer’s Disease a Liver Disease of the Brain?

Is Alzheimer’s Disease a Liver Disease of the Brain?

Functional module detection through integration of single-cell RNA sequencing data with protein–protein interaction networks

Exercise combined with a probiotics treatment alters the microbiome, but moderately affects signalling pathways in the liver of male APP/PS1 transgenic mice

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