Alzheimer’s is a degenerative disease characterized by the build-up of amyloid protein plaques in the brain. There are two conflicting theories for the cause of Alzheimer’s disease – the first being that the build up of the amyloid plaques directly causes the disease, and the second being that metabolic defects initiate the build-up of protein. More recent evidence has supported the theory that a metabolic defect within the mitochondria may cause the disease.

The worm species C. elegans was engineered to express the human form of the Aβ protein that builds up to form the amyloid plaques in Alzheimer’s. Even though protein aggregates were observed in the worms on day 12, defects in energy metabolism and mitochondrial electron transport were observed when the worms were very young. In this study, the biological mechanisms causing the aggregation of protein were investigated.

The engineered C. elegans suffer from significant energy metabolism disruption early in their lives. To determine which energy substrates were impacted, the levels of metabolites in the engineered worms were compared to age-matched controls. The worms displayed oxidative protein damage, specifically in the mitochondria, which began on day four. The Tricarboxylic acid (TCA) cycle was also impaired.

Interestingly, metabolic failure occurred before any increase in protein aggregate was detectable. This suggests that metabolic failure is both an early and causative event in the formation of Alzheimer’s disease, which induces protein aggregation as a secondary event.

Treatment with the anti-diabetes drug Metformin reduced protein aggregation and increased the lifespan of the mice. These findings suggest that mitochondrial dysfunction may be the most promising stage of the disease to intervene at.

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