Please use this identifier to cite or link to this item: https://doi.org/10.7554/eLife.50069
Title: Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta
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 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
ALPHA-KETOGLUTARATE DEHYDROGENASE
MILD COGNITIVE IMPAIRMENT
CYTOCHROME-C-OXIDASE
OXIDATIVE STRESS
ALZHEIMER-DISEASE
HYDROGEN-PEROXIDE
GENE-EXPRESSION
MOUSE MODEL
LIFE-SPAN
PROTEIN
Issue Date: 15-Oct-2019
Publisher: ELIFE SCIENCES PUBLICATIONS LTD
Citation: 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 (2019-10-15). Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta. ELIFE 8. ScholarBank@NUS Repository. https://doi.org/10.7554/eLife.50069
Abstract: © Teo et al. 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 (Ab)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Ab peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Ab-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Ab 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 Ab-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Ab-induced pathology and a promising target for intervention.
Source Title: ELIFE
URI: https://scholarbank.nus.edu.sg/handle/10635/170349
ISSN: 2050084X
DOI: 10.7554/eLife.50069
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