Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elega...

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Published ineLife Vol. 8
Main Authors Teo, Emelyne, Ravi, Sudharshan, Barardo, Diogo, Kim, Hyung-Seok, Fong, Sheng, Cazenave-Gassiot, Amaury, Tan, Tsze Yin, Ching, Jianhong, Kovalik, Jean-Paul, Wenk, Markus R, Gunawan, Rudiyanto, Moore, Philip K, Halliwell, Barry, Tolwinski, Nicholas, Gruber, Jan
Format Journal Article
LanguageEnglish
Published England eLife Science Publications, Ltd 15.10.2019
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
Subjects
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Aggregates
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer's disease
Amino acids
amyloid beta
Amyloid beta-Peptides - genetics
Amyloid beta-Peptides - metabolism
Amyloid beta-protein
Animals
Animals, Genetically Modified
Antidiabetics
Antioxidants
Bioengineering
Caenorhabditis elegans
Caenorhabditis elegans - drug effects
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Carbonyl compounds
Citric Acid Cycle - drug effects
Citric Acid Cycle - genetics
Computational neuroscience
Computer simulation
Defects
Diabetes mellitus
Disease Models, Animal
Elderly
Enzymes
Etiology
Etiology (Medicine)
Gene expression
Genetic aspects
Genetic engineering
Geriatrics
Health aspects
Humans
Hypoglycemic agents
Hypoglycemic Agents - pharmacology
Hypotheses
Insulin
Ketoglutarate Dehydrogenase Complex - genetics
Ketoglutarate Dehydrogenase Complex - metabolism
Ketoglutaric acid
Life span
Lipids
Metabolic Flux Analysis
Metabolism
Metabolomics
Metformin
Metformin - pharmacology
Mitochondria
Mitochondria - drug effects
Mitochondria - genetics
Mitochondria - metabolism
Nematodes
Nervous system diseases
Neurodegenerative diseases
Neurons
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Neurophysiology
Neuroscience
Neurosciences
Oxidative stress
Oxoglutarate dehydrogenase (lipoamide)
Pathogenesis
Peptides
Protein Aggregates - drug effects
Protein Carbonylation
Protein interaction
Proteins
Stress, Physiological - drug effects
Stress, Physiological - genetics
TCA cycle
Tricarboxylic acid cycle
United States
United States > US
Singapore
C. elegans
TCA cycle
mitochondria
neuroscience
metformin
metabolism
amyloid beta
Online AccessGet full text

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Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aβ-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aβ-induced pathology and a promising target for intervention.
AbstractList Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aβ-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aβ-induced pathology and a promising target for intervention.
Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aβ-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aβ-induced pathology and a promising target for intervention.
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (A[beta])-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human A[beta] peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this A[beta]-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level A[beta] expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed A[beta]-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in A[beta]-induced pathology and a promising target for intervention.
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aβ-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aβ-induced pathology and a promising target for intervention.
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aβ-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aβ-induced pathology and a promising target for intervention.Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aβ-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aβ-induced pathology and a promising target for intervention.
Audience Academic
Author Tan, Tsze Yin
Fong, Sheng
Cazenave-Gassiot, Amaury
Gunawan, Rudiyanto
Tolwinski, Nicholas
Ravi, Sudharshan
Kim, Hyung-Seok
Ching, Jianhong
Halliwell, Barry
Barardo, Diogo
Gruber, Jan
Moore, Philip K
Wenk, Markus R
Teo, Emelyne
Kovalik, Jean-Paul
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/31610847$$D View this record in MEDLINE/PubMed
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Keywords C. elegans
TCA cycle
mitochondria
neuroscience
metformin
metabolism
amyloid beta
Language English
License http://creativecommons.org/licenses/by/4.0
2019, Teo et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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Snippet Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key...
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key...
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SubjectTerms Advertising executives
Aggregates
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer's disease
Amino acids
amyloid beta
Amyloid beta-Peptides - genetics
Amyloid beta-Peptides - metabolism
Amyloid beta-protein
Animals
Animals, Genetically Modified
Antidiabetics
Antioxidants
Bioengineering
Caenorhabditis elegans
Caenorhabditis elegans - drug effects
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Carbonyl compounds
Citric Acid Cycle - drug effects
Citric Acid Cycle - genetics
Computational neuroscience
Computer simulation
Defects
Diabetes mellitus
Disease Models, Animal
Elderly
Enzymes
Etiology
Etiology (Medicine)
Gene expression
Genetic aspects
Genetic engineering
Geriatrics
Health aspects
Humans
Hypoglycemic agents
Hypoglycemic Agents - pharmacology
Hypotheses
Insulin
Ketoglutarate Dehydrogenase Complex - genetics
Ketoglutarate Dehydrogenase Complex - metabolism
Ketoglutaric acid
Life span
Lipids
Metabolic Flux Analysis
Metabolism
Metabolomics
Metformin
Metformin - pharmacology
Mitochondria
Mitochondria - drug effects
Mitochondria - genetics
Mitochondria - metabolism
Nematodes
Nervous system diseases
Neurodegenerative diseases
Neurons
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Neurophysiology
Neuroscience
Neurosciences
Oxidative stress
Oxoglutarate dehydrogenase (lipoamide)
Pathogenesis
Peptides
Protein Aggregates - drug effects
Protein Carbonylation
Protein interaction
Proteins
Stress, Physiological - drug effects
Stress, Physiological - genetics
TCA cycle
Tricarboxylic acid cycle
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Title Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta
URI https://www.ncbi.nlm.nih.gov/pubmed/31610847
https://www.proquest.com/docview/2310953603
https://www.proquest.com/docview/2305801247
https://pubmed.ncbi.nlm.nih.gov/PMC6794093
https://doaj.org/article/eb3eb4a1028f48789394b89e79678ebd
Volume 8
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