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 (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.
Highlights
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease, that is clinically characterized by the formation of amyloid-beta (Ab) plaques and aggregates of hyperphosphorylated tau protein in the brain (Mirra et al, 1991)
To determine which energy substrates were affected in GRU102, we followed a targeted metabolomics approach, comparing intermediary metabolites involved in energy production between agematched GRU102 and its transgenic controls (GRU101)
We found that levels of the common energy precursor C2 were significantly reduced in old GRU102 compared to age-matched GRU101 controls (Figure 1A, Figure 1—figure supplement 1), reflecting a low energy status in old GRU102
Summary
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease, that is clinically characterized by the formation of amyloid-beta (Ab) plaques and aggregates of hyperphosphorylated tau protein in the brain (Mirra et al, 1991). Neuroscience mitochondrial functions including energy metabolism have consistently been observed in the brain (Gibson et al, 1998; Gibson et al, 1999; Muller et al, 2010) and in non-neuronal cells derived from AD subjects, including in fibroblasts and platelets (Bosetti et al, 2002; Blass and Gibson, 1992; Cardoso et al, 2004; Curti et al, 1997; Parker et al, 1994; Swerdlow, 2012) These findings form part of an emerging story that there is an important metabolic component to the etiology of AD (de la Monte and Wands, 2008), and that these metabolic defects may precede Ab aggregate formation (Yao et al, 2009; Ye et al, 2012). Intranasal insulin treatment has been shown to ameliorate AD pathology in a transgenic rat model and to improve mild cognitive impairment (MCI) in patients (Craft et al, 2012; Guo et al, 2017; Stanley et al, 2016; Craft et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
