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

Elife. 2019 Oct 15;8:e50069. doi: 10.7554/eLife.50069.


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.

Keywords: C. elegans; TCA cycle; amyloid beta; metabolism; metformin; mitochondria; neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Citric Acid Cycle / drug effects
  • Citric Acid Cycle / genetics*
  • Disease Models, Animal
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Ketoglutarate Dehydrogenase Complex / genetics
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Metabolic Flux Analysis
  • Metformin / pharmacology
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Protein Aggregates / drug effects
  • Protein Carbonylation
  • Stress, Physiological / drug effects
  • Stress, Physiological / genetics*


  • Amyloid beta-Peptides
  • Hypoglycemic Agents
  • Protein Aggregates
  • Metformin
  • Ketoglutarate Dehydrogenase Complex