Dataset Information

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

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 (A?)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human A? peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this A?-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level A? 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?-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?-induced pathology and a promising target for intervention.

SUBMITTER: Teo E

PROVIDER: S-EPMC6794093 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Metabolic stress is a primary pathogenic event in transgenic <i>Caenorhabditis elegans</i> expressing pan-neuronal human amyloid beta.

Teo Emelyne E Ravi Sudharshan S Barardo Diogo D Kim Hyung-Seok HS Fong Sheng S Cazenave-Gassiot Amaury A Tan Tsze Yin TY Ching Jianhong J Kovalik Jean-Paul JP Wenk Markus R MR Gunawan Rudiyanto R Moore Philip K PK Halliwell Barry B Tolwinski Nicholas N Gruber Jan J

eLife 20191015

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 <i>Caenorhabditis elegans</i> 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 ...[more]

PMID: 31610847

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Project description:Liuwei Dihuang (LWDH), a classic Chinese medicinal formula, has been used to improve or restore declined functions related to aging and geriatric diseases, such as impaired mobility, vision, hearing, cognition and memory. Here, we report on the effect and possible mechanisms of LWDH mediated protection of ?-amyloid (A?) induced paralysis in Caenorhabditis elegans using ethanol extract (LWDH-EE) and water extract (LWDH-WE). Chemical profiling and quantitative analysis revealed the presence of different levels of bioactive components in these extracts. LWDH-WE was rich in polar components such as monosaccharide dimers and trimers, whereas LWDH-EE was enriched in terms of phenolic compounds such as gallic acid and paeonol. In vitro studies revealed higher DPPH radical scavenging activity for LWDH-EE as compared to that found for LWDH-WE. Neither LWDH-EE nor LWDH-WE were effective in inhibiting aggregation of A? in vitro. By contrast, LWDH-EE effectively delayed A? induced paralysis in the transgenic C. elegans (CL4176) model which expresses human A?1-42. Western blot revealed no treatment induced reduction in A? accumulation in CL4176 although a significant reduction was observed at an early stage with respect to ?-amyloid deposition in C. elegans strain CL2006 which constitutively expresses human A?1-42. In addition, LWDH-EE reduced in vivo reactive oxygen species (ROS) in C. elegans (CL4176) that correlated with increased survival of LWDH-EE treated N2 worms under juglone-induced oxidative stress. Analysis with GFP reporter strain TJ375 revealed increased expression of hsp16.2::GFP after thermal stress whereas a minute induction was observed for sod3::GFP. Quantitative gene expression analysis revealed that LWDH-EE repressed the expression of amy1 in CL4176 while up-regulating hsp16.2 induced by elevating temperature. Taken together, these results suggest that LWDH extracts, particularly LWDH-EE, alleviated ?-amyloid induced toxicity, in part, through up-regulation of heat shock protein, antioxidant activity and reduced ROS in C. elegans.

Dataset Information

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

Publications

Metabolic stress is a primary pathogenic event in transgenic <i>Caenorhabditis elegans</i> expressing pan-neuronal human amyloid beta.

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