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

Teo, E.; Ravi, S.; Barardo, D.; Kim, H.-S.; Fong, S.; Cazenave-Gassiot, A.; Tan, T. Y.; Ching, J.; Kovalik, J.-P.; Wenk, M. R.; Gunawan, R.; Moore, P. K.; Halliwell, B.; Tolwinski, N.; Gruber, J.

doi:10.1101/708537

bioRxiv · 10.1101/708537

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

Teo, E.·Ravi, S.·Barardo, D.·Kim, H.-S.·Fong, S.·Cazenave-Gassiot, A.·Tan, T. Y.·Ching, J.·Kovalik, J.-P.·Wenk, M. R.·Gunawan, R.·Moore, P. K.·Halliwell, B.·Tolwinski, N.·Gruber, J.

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Abstract

Alzheimers 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 a deeper analysis of these metabolic changes associated with A{beta}-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level A{beta} expression. In particular, GRU102 show reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects are associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurs before any significant increase in global protein aggregate is detectable. Treatment with an antidiabetes drug, Metformin, reverses A{beta}-induced metabolic defects, reduces protein aggregation and normalizes the lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in AD pathology and a promising target for intervention.

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Teo, E., Ravi, S., Barardo, D., Kim, H.-S., Fong, S., Cazenave-Gassiot, A., Tan, T. Y., Ching, J., Kovalik, J.-P., Wenk, M. R., Gunawan, R., Moore, P. K., Halliwell, B., Tolwinski, N., Gruber, J.. 2019-07-19. Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing neuronal human amyloid-β. https://doi.org/10.1101/708537

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