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dc.contributor.author
Teo, Emelyne
dc.contributor.author
Ravi, Sudharshan
dc.contributor.author
Barardo, Diogo
dc.contributor.author
Kim, Hyung-Seok
dc.contributor.author
Fong, Sheng
dc.contributor.author
Cazenave-Gassiot, Amaury
dc.contributor.author
Tan, Tsze Yin
dc.contributor.author
Ching, Jianhong
dc.contributor.author
Kovalik, Jean-Paul
dc.contributor.author
Wenk, Markus R.
dc.contributor.author
Gunawan, Rudiyanto
dc.contributor.author
Moore, Philip K.
dc.contributor.author
Halliwell, Barry
dc.contributor.author
Tolwinski, Nicholas
dc.contributor.author
Gruber, Jan
dc.date.accessioned
2019-10-21T10:01:06Z
dc.date.available
2019-10-20T03:02:08Z
dc.date.available
2019-10-21T10:01:06Z
dc.date.issued
2019-10-15
dc.identifier.other
10.7554/eLife.50069
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/371746
dc.identifier.doi
10.3929/ethz-b-000371746
dc.description.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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
eLife Sciences Publications
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
eLife
ethz.journal.volume
8
en_US
ethz.pages.start
e50069
en_US
ethz.size
25 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
MetAge: Metabolic network analysis for understanding the biology of ageing
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Cambridge
en_US
ethz.publication.status
published
en_US
ethz.grant.agreementno
163390
ethz.grant.fundername
SNF
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.program
ethz.date.deposited
2019-10-20T03:02:29Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2019-10-21T10:01:20Z
ethz.rosetta.lastUpdated
2020-02-15T22:08:25Z
ethz.rosetta.versionExported
true
ethz.COinS
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