Improving mitochondria reverses protein accumulation in aging and Alzheimer's

It has long been known that a hallmark of Alzheimer's disease and most other neurodegenerative diseases is the formation of insoluble protein aggregates in the brain. Even with normal aging without disease, insoluble proteins accumulate.

To date, approaches to the treatment of Alzheimer's disease have not taken into account the contribution of protein insolubility as a general phenomenon, but have focused on one or two insoluble proteins. Recently, researchers at the Buck Institute completed a systematic study in worms that paints a complex picture of the relationships between insoluble proteins in neurodegenerative diseases and aging. In addition, the work showed an intervention that could reverse the toxic effects of the aggregates by improving mitochondrial health.

"Our findings suggest that targeting insoluble proteins may provide a strategy for preventing and treating various age-related diseases," said Edward Anderton, Ph.D., a postdoctoral fellow in Gordon Lithgow's laboratory and one of the first authors of the study published in GeroScience magazine.

"Our study shows how maintaining healthy mitochondria can combat protein aggregation associated with both aging and Alzheimer's disease," said Manish Chamoli, Ph.D., a postdoctoral fellow in the laboratory of Gordon Lithgow and Julie Andersen, and one of the first authors of the study. "By improving mitochondrial health, we can potentially slow or reverse these harmful effects, offering new treatments for both aging and age-related diseases."

The results confirm the gerontological hypothesis

The strong connection between insoluble proteins that contribute to normal aging and disease also supports a broader picture of how aging and related diseases occur.

"We would argue that this work does support the gerontological hypothesis that there is a common pathway to both Alzheimer's disease and aging itself. Aging causes disease, but the factors that lead to disease occur very early in life," - said Gordon Lithgow, Ph.D., Baca Professor, vice president for academic affairs and senior author of the study.

The fact that the team discovered a core insoluble proteome enriched in numerous proteins that had not previously been considered creates new targets for research, Lithgow said. "In some ways it raises the question of whether we should be looking at what Alzheimer's disease looks like in very young people," he said.

Beyond amyloid and tau

Most research into Alzheimer's disease so far has focused on the accumulation of two proteins: amyloid beta and tau. However, there are actually thousands of other proteins in these insoluble aggregates, Anderton said, and their role in Alzheimer's disease was unknown. In addition, their laboratory and others have observed that during the normal aging process without disease, an accumulation of insoluble proteins also occurs. These insoluble proteins from old animals, when mixed with amyloid beta in vitro, accelerate amyloid aggregation.

The team asked themselves what the connection was between the accumulation of Alzheimer's aggregates and aging without the disease. Focusing on amyloid beta, they used a strain of the microscopic worm Caenorhabditis elegans, long used in aging research, that was genetically modified to produce human amyloid protein.

Anderton said the team suspected that amyloid beta might cause some degree of insolubility in other proteins. "We found that amyloid beta causes massive insolubility, even in very young animals," Anderton said. They found that there is a subset of proteins that appear to be highly vulnerable to insolubility, either due to the addition of amyloid beta or during the normal aging process. They called this vulnerable subset the “core insoluble proteome.”

The team also demonstrated that the core of the insoluble proteome is filled with proteins that have already been linked to various neurodegenerative diseases beyond Alzheimer's, including Parkinson's, Huntington's, and prion diseases.

"Our study suggests that amyloid may act as a driver of this normal age-related aggregation," Anderton said. "We now have clear evidence, I think for the first time, that both amyloid and aging affect the same proteins in similar ways. It's quite possible a vicious circle where aging causes insolubility, and amyloid beta also causes insolubility, and they just reinforce each other."

Amyloid protein is highly toxic to worms, and the team wanted to find a way to reverse this toxicity. "Because hundreds of mitochondrial proteins become insoluble both during aging and after expression of amyloid beta, we thought if we could improve the quality of mitochondrial proteins with a compound, then perhaps we could reverse some of the negative effects of amyloid beta," Anderton said. That's exactly what they found using urolithin A, a natural metabolite produced in the gut when we eat raspberries, walnuts and pomegranates that is known to improve mitochondrial function: it significantly delayed the toxic effects of amyloid beta.

"What was clear from our data was the importance of mitochondria," Anderton said. One conclusion, the authors say, is that mitochondrial health is critical to overall health. "Mitochondria have a strong connection with aging. They have a strong connection with amyloid beta," he said. "I think our study is one of the few that shows that the insolubility and aggregation of these proteins may be a link between the two processes."

"Because mitochondria are so important to all of this, one way to break the cycle of decline is to replace damaged mitochondria with new mitochondria," Lithgow said. "How to do this? You need to exercise and eat a healthy diet."