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.
Highlights
Alzheimer disease (AD) is a neurological disorder characterized by progressive memory impairment and cognitive deficits
We have developed a novel C. elegans strain with constitutive pan-neuronal Aβ1–42 expression and aimed to clarify the temporal relationships between energy metabolism, mitochondrial dysfunction and neurodegeneration in Alzheimer Disease (AD) pathogenesis
Most of the phenotypes observed are consistent with predominately neuronal expression. This strain suffered from shortened lifespan and reduced health-span, and exhibited neuromuscular and behavioural dysfunction including internal hatching, constipation, defects in pharyngeal pumping, abnormal oscillatory head movements and middle-age-onset sensorimotor deficits
Summary
Alzheimer disease (AD) is a neurological disorder characterized by progressive memory impairment and cognitive deficits. We have developed a novel C. elegans strain with constitutive pan-neuronal Aβ1–42 expression and aimed to clarify the temporal relationships between energy metabolism, mitochondrial dysfunction and neurodegeneration in AD pathogenesis. To facilitate delineation of the temporal sequence of these events and for screening and intervention testing, we aimed at generating a strain that would exhibit progressive neuronal dysfunction and middle-age-onset behavioural phenotypes. To this end, we first constitutively expressed full-length human Aβ1–42 peptide in all nematode neurons at different gene www.nature.com/scientificreports/. After characterizing the behavioural deficits in the Aβ-expressing nematodes, we investigated the temporal relationships between energy metabolism, mitochondrial dysfunction and neurodegeneration
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