Metabolic dysfunction of mitochondria responsible for Alzheimer's disease

Scientists have said metabolic dysfunction, specifically of mitochondria, causes neurodegenerative disease Alzheimer's in the elderly.

Alzheimer's researcher of Research Center and Advanced Studies (CINVESTAV), shows a victims' brain

Metabolic dysfunction, particularly a dysfunction of mitochondria, is a primary cause of Alzheimer's disease in adults, research has revealed.

A team of researchers from Yale-NUS College said metabolic defects occurred well before any significant increase in the amount of amyloid-beta protein could be detected.

There are currently two competing hypotheses that explain the cause of Alzheimer's – the accumulation of amyloid-beta protein in the brain and metabolic dysfunction being responsible for the most common neurodegenerative disease affecting the elderly worldwide.

In the research published in eLife, scientists used C. elegans to identify these changes because it shares many similarities at the molecular level with human cells, and discovered that treatment of the worms with a common anti-diabetes drug (Metformin) reversed these metabolic defects and normalized their healthspan.

Lead author Jan Gruber, Ph.D., assistant professor, said mitochondrial dysfunction had been proposed as a key event in the etiology of AD.

The researcher said his team had previously modelled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic C. elegans strain by expressing human Aβ peptide specifically in neurons (GRU102) and now focused on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction.

"Integrating metabolomics, transcriptomics, and computational modelling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed the reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase," he explained.

The research suggested these defects were associated with elevation of protein carbonyl content specifically in mitochondria, and its failure followed a significant increase in global protein aggregate.

The researcher said it was better to adopt a preventative strategy by targeting metabolic defects, especially mitochondrial defects, well before protein aggregates started building.

He further explained that metabolic and mitochondrial dysfunctions should be viewed as fundamental features of ageing in general and that age-dependent diseases, including Alzheimer's, maybe prevented by targeting the mechanisms of ageing rather than treating individual diseases after symptoms occur.

Alzheimer's is one of the most common causes of dementia and one in 10 people aged 60 years or above in Singapore is believed to be suffering from the condition.

Scientists even after more than twenty years of spending billions of dollars in research efforts worldwide are still unable to identify the exact causes of Alzheimer's.