Energy crisis precedes global metabolic failure in a novel Caenorhabditis elegans Alzheimer Disease model

Abstract

Alzheimer Disease (AD) is a progressive neurological disorder characterized by the deposition of amyloid beta (Aβ), predominantly the Aβ1–42 form, in the brain. Mitochondrial dysfunction and impaired energy metabolism are important components of AD pathogenesis. However, the causal and temporal relationships between them and AD pathology remain unclear. Using a novel C. elegans AD strain with constitutive neuronal Aβ1–42 expression that displays neuromuscular defects and age-dependent behavioural dysfunction reminiscent of AD, we have shown that mitochondrial bioenergetic deficit is an early event in AD pathogenesis, preceding dysfunction of mitochondrial electron transfer chain (ETC) complexes and the onset of global metabolic failure. These results are consistent with an emerging view that AD may be a metabolic neurodegenerative disease, and also confirm that Aβ-driven metabolic and mitochondrial effects can be reproduced in organisms separated by large evolutionary distances.

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

“…In particular, temperature-inducible strains which, upon induction, express high levels of Aβ in muscle, form obvious Aβ aggregates, exhibit rapid paralysis and die within 2-3 days 30–32 . Strains with a comparatively low-level of neuronal Aβ expression do not produce obvious aggregates and typically display milder effects, such as a reduction in egg-laying, progressive chemotaxis defects, neuronal loss and a 10-20% reduction in lifespan 31,33,34 . Different strains therefore serve as useful tools to study different aspects of AD (late-stage, aggregate-driven pathologies in the more severely affected strains vs. early-stage AD in strains with later and milder phenotypes).…”

“…To study the temporal sequence of events underlying Aβ-mediated toxicity, especially the early events affecting mitochondrial metabolism, we have created a novel transgenic C. elegans strain with constitutive pan-neuronal expression of low-levels of human Aβ 1-42 (GRU102) 33 . Similar to previous transgenic strains expressing Aβ in neurons, GRU102 display comparatively mild phenotypes including failure in chemotaxis, with neuromuscular and behavioral defects that become more pronounced with age.…”

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

“…In addition, dvIs14; gsr-1(m+,z-) animals showed a fully penetrant egg-laying phenotype, most likely reflecting the lack of contractility of the uterine and vulva muscles which are responsible for egg extrusion (Figure 3d). The genetic interaction between Ab protein and the gsr-1 mutation was also found in worms expressing human Ab in the nervous system from the ganIs2 [Punc-119::Ab] transgene 35 . Thus, the gsr-1(m+,z-) mutation causes a strong developmental delay in a ganIs2 genetic background ( Figure 3e) which correlated with a higher sensitivity to DEM of ganIs2 nematodes (Figure 3f).…”

C. elegansgenetic background modifies the core transcriptional response in an α-synuclein model of Parkinson’s disease

“…Similar phenotypic effects are observed in other C. elegans models of protein misfolding disease. For example, transgenic worms expressing polyQ proteins and Aβ both show a significantly shortened lifespan (Gidalevitz et al 2013;Fong et al 2016). A reduced lifespan could therefore be a general toxicity phenotype, providing an indirect measure of organismal dysfunction caused by misfolded protein aggregations in the body wall.…”