A team of researchers led by Yale-NUS College says it has found evidence that metabolic dysfunction is a primary cause of Alzheimer’s disease.
Two competing hypotheses are currently proposed to explain the cause of Alzheimer’s: the first is focused on the accumulation of amyloid-beta protein in the brain as the primary cause; while a second and more recent hypothesis proposes that metabolic dysfunction, specifically a dysfunction of the mitochondria, is responsible.
In a new study (“Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta”) published in eLife, Jan Gruber, PhD, assistant professor, and colleagues discovered that metabolic defects occur well before any significant increase in the amount of amyloid-beta protein could be detected. The researchers used C. elegans to identify these changes because it shares many similarities at the molecular level with human cells. The team also found that treatment of the worms with a common anti-diabetes drug (Metformin) reversed these metabolic defects and normalized the worms’ healthspan and lifespan.
“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 C. 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,” the investigators wrote.
“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.”
“Current trials of Alzheimer’s drugs targeting proteins have failed despite billions of dollars being invested. Based on the emerging strong links between mitochondrial dysfunction and Alzheimer’s pathology, it might be better to adopt a preventative strategy by targeting metabolic defects, especially mitochondrial defects, directly and early, well before protein aggregates are even present,” Gruber said.
He further explained that metabolic and mitochondrial dysfunctions should be viewed as fundamental features of aging in general and that age-dependent diseases, including Alzheimer’s, should, therefore, be viewed as manifestations of aging. Hence, it may be easier to prevent or treat age-dependent diseases by targeting the mechanisms of aging rather than treating individual diseases after symptoms occur.