Rejuvenating' mitochondria may help fight toxic proteins in Alzheimer's

Researchers have used worm models to understand why proteins clump together in harmful ways, something that has been associated with Alzheimer’s disease.

• The currently agreed-on premise is that the clumping of certain proteins in the brain is a driving factor for Alzheimer’s disease.
• Researchers from The Buck Institute for Research in Novato, CA, now say there are other proteins in these brain clumps that have been largely ignored so far, and that could also play a role in the development of this form of dementia.
• Using a worm model, scientists found that both the natural aging process and beta-amyloid drive some proteins to become insoluble.
• Researchers used a compound to boost the quality of mitochondrial health in the proteins that had become insoluble, helping to delay the toxic effects of beta-amyloid.

Although scientists still do not know the exact cause of Alzheimer’s disease, most agree that the clumping of certain proteins — beta-amyloid and tau — in the brain characterize the disease.

“The unifying feature of neurodegenerative diseases of aging is the accumulation of large protein clumps in the brain which we term insoluble protein aggregates,” Edward Anderton, PhD, a postdoctoral researcher at The Buck Institute for Research on Aging in California and co-first author of a study recently published in the journal GeroScience, explained to Medical News Today.

“In Alzheimer’s disease, the [beta-amyloid] protein forms aggregates called plaques, and these are tightly associated with areas of neuronal death and brain inflammation causing disease,” he noted.

However, Anderton added, these plaques contain hundreds of additional proteins which have been largely ignored until now.

For this reason, he and other researchers from The Buck Institute for Research on Aging in California decided to examine how the accumulation of insoluble proteins, in general, might accelerate Alzheimer’s disease.

Using a worm model, scientists found that both the natural aging process and beta-amyloid drive other proteins to become insoluble.

Researchers then used a compound to boost the quality of mitochondrial health in the proteins that had become insoluble, effectively delaying the toxic effects of beta-amyloid.

Mitochondria, the so-called powerhouses of the cell, have recently become a focus point in Alzheimer’s research, as scientist have been trying to see whether “repairing” mitochondria that stop functioning well with age might help preserve brain health.

What is protein clumping?

According to Manish Chamoli, PhD, research scientist at The Buck Institute for Research on Aging in California and co-first author of this study, proteins are like tiny machines in our cells that need to be a specific shape to work correctly.

“Imagine if you had a key that got bent and no longer fit into its lock — that’s similar to what happens when proteins lose their shape,” Chamoli explained to MNT. “These misshapen proteins start sticking together and form insoluble protein aggregates. Proteins can lose their shape due to various factors like stress, aging, or damage.”

“Our cells have evolved ways to either refold the proteins into the correct shape or degrade them when they’re too damaged to be refolded,” he continued.

In conditions such as Alzheimer’s disease, however, the brain does not correctly dispose of such proteins.

“In laboratory organisms, such as the microscopic worm Caenorhabditis elegansTrusted Source, our lab and other labs around the world have observed that, as these worms age, they accumulate clumps of insoluble proteins,“ Chamoli told us.

“Likewise, it’s well established that Alzheimer’s disease patients’ brains accumulate protein aggregates,” he added.

Why do proteins clump in the brain?

As insoluble proteins do accumulate in the brain during normal disease-free aging, Chamoli, Anderton, and their team wanted to know what was the connection between brain protein clumps in normal aging and Alzheimer’s disease.

Using a worm model, scientists discovered that beta-amyloid causes a massive amount of insolubility in other proteins, especially in a subset of proteins researchers called “the core insoluble proteome.“

According to researchers, the insoluble proteins found in the core insoluble proteome have already been linked to other neurodegenerative conditions including Parkinson’s disease and Huntington’s disease.

“Data suggest there may be a causal role for the insoluble proteome in Alzheimer’s disease pathogenesis,” Anderton said. “For example, insoluble protein extracts from old but not young animals accelerate the aggregation of [beta-amyloid].”

“We questioned if the reverse was also true: Can [beta-amyloid] drive the insolubility of proteins that tend to aggregate during aging? Our data are consistent with the notion that [beta-amyloid] and age-related changes interact in a destructive feedforward cycle, leading to an acceleration of protein insolubility in Alzheimer’s disease.”– Edward Anderton, PhD

Can boosting mitochondrial health prevent toxic aggregate formation?

Next, researchers wanted to find a way to potentially reverse how beta-amyloid helps drive the insolubility of proteins.

As many mitochondrial proteins become insoluble during natural aging and beta-amyloid influence, they hypothesized that boosting mitochondrial protein quality might reverse some of beta-amyloid’s negative effects.

“Mitochondria contain a specialized energy-producing complex of proteins called the electron transport chain which is the primary way our cells use food to produce energy,” Chamoli said. “We found that the proteins of the electron transport chain were driven to become insoluble when we exposed them to [beta-amyloid].”

“It has been known for some time that mitochondria can be negatively impacted by [beta-amyloid] but we show that this is likely due to protein insolubility,” he continued. “Luckily, cells possess a way to recycle damaged mitochondria through a process called mitophagy. Our lab and others study a small molecule that boosts mitophagy to rejuvenate mitochondria.”

To do this, they chose urolithin A — a metabolite compound found in the gut microbiome. Pomegranates, walnuts, strawberries, raspberries, chia seeds, hemp seeds, and almonds are all foods rich in urolithin A.

“We reasoned that using a pharmacological approach to clear away the insoluble proteins from mitochondria could prevent some of the toxic effects of [beta-amyloid] and that’s exactly what we found,” Anderton said.

Potential for new therapeutic interventions for Alzheimer’s

MNT also spoke with Verna R. Porter, MD, a board-certified neurologist and director of the Dementia, Alzheimer’s Disease and Neurocognitive Disorders at Pacific Neuroscience Institute in Santa Monica, CA, about this study.

Porter, who was not involved in the research, said these findings suggest that beta-amyloid likely contributes to widespread protein insolubility, particularly affecting mitochondrial proteins and that this insolubility mirrors changes seen in aging.

“The discovery that targeting mitochondrial health can mitigate some of these aging effects suggests a potential novel approach to addressing Alzheimer’s disease,” she added.

Porter said that with the study’s findings indicating that improving mitochondrial health may reverse some negative effects of beta-amyloid toxicity, this could pave the way for several potential interventions including pharmacological approaches, nutritional supplements, and lifestyle modifications.

“It would be interesting to conduct clinical trials to test the efficacy of mitochondrial health-boosting compounds in Alzheimer’s disease patients, including compounds like urolithin A and other mitochondrial enhancers,” Porter continued.

“Further exploration of the mechanisms by which [beta-amyloid] disrupts mitochondrial function and leads to protein insolubility could help elucidate these pathways, revealing additional potential therapeutic targets,” she noted.

https://www.medicalnewstoday.com/articles/rejuvenating-mitochondria-may-help-fight-toxic-proteins-in-alzheimers#Can-boosting-mitochondrial-health-prevent-toxic-aggregate-formation?