Cerebral Fructose Metabolism as a Potential Mechanism Driving Alzheimer’s Disease

Johnson, Richard J.; Gómez‐Pinilla, Fernando; Nagel, Maria A.; Nakagawa, Takahiko; Rodríguez‐Iturbe, Bernardo; Sánchez‐Lozada, Laura G.; Tolan, Dean R.; Lanaspa, Miguel A.

doi:10.3389/fnagi.2020.560865

Cited by 45 publications

(61 citation statements)

References 174 publications

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“…In turn, the low level of intracellular phosphate activates adenosine monophosphate (AMP) deaminase, with consequent degradation of AMP to inosine monophosphate and, eventually, uric acid. The consumption of AMP caused by the activation of AMP deaminase-2 reduces the cell’s ability to restore ATP levels and further stimulates uric acid production [ 8 , 52 , 53 ]. Uric acid, while being an anti-oxidant in the extracellular environment, has proinflammatory activity in the intracellular environment and can induce NF-kB activation and oxidative stress [ 54 , 55 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

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Fructose Removal from the Diet Reverses Inflammation, Mitochondrial Dysfunction, and Oxidative Stress in Hippocampus

et al. 2021

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Young age is often characterized by high consumption of processed foods and fruit juices rich in fructose, which, besides inducing a tendency to become overweight, can promote alterations in brain function. The aim of this study was therefore to (a) clarify brain effects resulting from fructose consumption in juvenile age, a critical phase for brain development, and (b) verify whether these alterations can be rescued after removing fructose from the diet. Young rats were fed a fructose-rich or control diet for 3 weeks. Fructose-fed rats were then fed a control diet for a further 3 weeks. We evaluated mitochondrial bioenergetics by high-resolution respirometry in the hippocampus, a brain area that is critically involved in learning and memory. Glucose transporter-5, fructose and uric acid levels, oxidative status, and inflammatory and synaptic markers were investigated by Western blotting and spectrophotometric or enzyme-linked immunosorbent assays. A short-term fructose-rich diet induced mitochondrial dysfunction and oxidative stress, associated with an increased concentration of inflammatory markers and decreased Neurofilament-M and post-synaptic density protein 95. These alterations, except for increases in haptoglobin and nitrotyrosine, were recovered by returning to a control diet. Overall, our results point to the dangerous effects of excessive consumption of fructose in young age but also highlight the effect of partial recovery by switching back to a control diet.

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Section: Discussionmentioning

confidence: 99%

“…Recently, different lines of evidence in animal models highlighted the marked effects of this sugar on brain structure and function [ 7 , 8 ]. In fact, long-term feeding with fructose can cause brain alterations such as insulin signaling [ 9 ], neurogenesis [ 10 ], and redox homeostasis, as well as neuroinflammation [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Fructose Removal from the Diet Reverses Inflammation, Mitochondrial Dysfunction, and Oxidative Stress in Hippocampus

et al. 2021

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“…APOE has been linked to the reduced efficiency in several brain pathways including as examples lipid transport and glucose metabolism. Recently, fructose metabolism in the brain has been proposed as a possible mechanism driving AD [ 10 ]. Dysfunction of many other metabolic pathways have been outlined as part of AD development and progression including changes in the metabolism of glucose [ 11 ], insulin [ 12 ], ketones [ 13 ], oxidative stress [ 14 , 15 ], fructose [ 10 ], and bile acids [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, fructose metabolism in the brain has been proposed as a possible mechanism driving AD [ 10 ]. Dysfunction of many other metabolic pathways have been outlined as part of AD development and progression including changes in the metabolism of glucose [ 11 ], insulin [ 12 ], ketones [ 13 ], oxidative stress [ 14 , 15 ], fructose [ 10 ], and bile acids [ 16 ]. Vitamine D [ 17 ] has, for example, been indicated as highly relevant in AD even suggesting that AD is a modern disease driven by changes in dietary lifestyle and its essence a metabolic disease [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

SMILE: systems metabolomics using interpretable learning and evolution

Sha

Čuperlović-Culf

2021

BMC Bioinformatics

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Background Direct link between metabolism and cell and organism phenotype in health and disease makes metabolomics, a high throughput study of small molecular metabolites, an essential methodology for understanding and diagnosing disease development and progression. Machine learning methods have seen increasing adoptions in metabolomics thanks to their powerful prediction abilities. However, the “black-box” nature of many machine learning models remains a major challenge for wide acceptance and utility as it makes the interpretation of decision process difficult. This challenge is particularly predominant in biomedical research where understanding of the underlying decision making mechanism is essential for insuring safety and gaining new knowledge. Results In this article, we proposed a novel computational framework, Systems Metabolomics using Interpretable Learning and Evolution (SMILE), for supervised metabolomics data analysis. Our methodology uses an evolutionary algorithm to learn interpretable predictive models and to identify the most influential metabolites and their interactions in association with disease. Moreover, we have developed a web application with a graphical user interface that can be used for easy analysis, interpretation and visualization of the results. Performance of the method and utilization of the web interface is shown using metabolomics data for Alzheimer’s disease. Conclusions SMILE was able to identify several influential metabolites on AD and to provide interpretable predictive models that can be further used for a better understanding of the metabolic background of AD. SMILE addresses the emerging issue of interpretability and explainability in machine learning, and contributes to more transparent and powerful applications of machine learning in bioinformatics.

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“…The Purine degradation pathway is induced by fructose through its rapid depletion of cellular ATP levels and activation of AMP deaminase (AMPD), eventually leading to the production of uric acid. Changes in the level of uric acid has been previously linked to the risk of dementia, with low levels associated with Parkinson's disease 34,31 and high levels of serum uric acid linked to vascular or mixed dementia and to a lesser extent AD 39 . Distance correlation analysis shows major differences in correlation partners for fructose with significant correlation with several other metabolites that are part of purine metabolism including ADP in addition to adenine, inosine and urea.…”

Section: Discussionmentioning

confidence: 99%

Signed Distance Correlation (SiDCo): A network analysis application of distance correlation for identifying metabolic networks disrupted in Dementia with Lewy Bodies

Čuperlović-Culf

Yılmaz

Akyol³

et al. 2021

Preprint

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INTRODUCTION Determining significant metabolic changes in Dementia with Lewy Bodies (DLB), a complex and multifactorial neurodegenerative disease, requires, in addition to the analysis of concentration changes, a deep understanding of functional modifications in the context of metabolic networks. METHODS Brain metabolomics data from DLB patients and controls was explored using novel correlation analysis approaches to identify metabolites with the largest changes in their network in the disease state. RESULTS Novel clustering and correlation network analysis shows major change in the metabolic network in DLB brain relative to matching controls with the largest interaction network alterations for fructose, propylene-glycol, pantothenate and O-acetylcarnitine in spite of no statistically significant changes in their concentrations. DISCUSSION Network and correlation analyses indicate major changes in the purine degradation pathway, propanoate and b-alanine metabolism as well as an increased role of fructose and reduced significance of glucose in DLB affected brain.

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Cerebral Fructose Metabolism as a Potential Mechanism Driving Alzheimer’s Disease

Cited by 45 publications

References 174 publications

Fructose Removal from the Diet Reverses Inflammation, Mitochondrial Dysfunction, and Oxidative Stress in Hippocampus

Fructose Removal from the Diet Reverses Inflammation, Mitochondrial Dysfunction, and Oxidative Stress in Hippocampus

SMILE: systems metabolomics using interpretable learning and evolution

Signed Distance Correlation (SiDCo): A network analysis application of distance correlation for identifying metabolic networks disrupted in Dementia with Lewy Bodies

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