It has long been known that Alzheimer's disease and most other neurodegenerative diseases are characterized by the clumping of insoluble protein clumps in the brain. Insoluble proteins accumulate even during normal aging without disease.
To date, treatments for Alzheimer's disease have not addressed the contribution of protein insolubility as a common phenomenon and have instead focused on one or two insoluble proteins. Buck researchers recently completed a systematic study in Caenorhabditis elegans that paints a complex picture of the relationship between insoluble proteins in neurodegenerative diseases and aging. Furthermore, this study demonstrated an intervention that can reverse the toxic effects of aggregates by promoting mitochondrial health.
Edward Anderton, Ph.D., a postdoctoral fellow in Gordon Lithgow's lab and co-lead author of the study, said: “Based on our findings, targeting insoluble proteins may be a promising candidate for a variety of age-related diseases. “This has the potential to provide strategies for prevention and treatment.” It will be published in his May 16 issue of the journal GeroScience.
“Our research shows how maintaining healthy mitochondria can combat protein aggregation associated with both aging and Alzheimer's disease,” said Gordon Lythgow and Julie Andersen. said Dr. Manish Chamoli, a researcher in the lab and co-lead author of the study. “Increasing mitochondrial health has the potential to slow or reverse these harmful effects, providing new ways to treat both aging and age-related diseases.”
Results support the geroscience hypothesis
The strong association between normal aging and disease-promoting insoluble proteins also provides evidence for a complete picture of how aging and age-related diseases develop.
We would argue that this study really supports the geriatric hypothesis that there is a common pathway between Alzheimer's disease and aging itself. Although aging accelerates the disease, the factors that set us on the path to disease actually occur very early on. ”
Gordon Lithgow.Dr. Buck, Professor, Vice President for Academic Affairs, and senior author of the study
The fact that the research team discovered a core insoluble proteome rich in a number of previously unconsidered proteins creates new targets for exploration, Lithgow said. “In some ways, this raises the flag about whether we should be thinking about what Alzheimer's disease looks like in very young people,” he says.
Beyond amyloid and tau
Most research into Alzheimer's disease to date has targeted the accumulation of two proteins: amyloid beta and tau. But there are actually thousands of other proteins in these insoluble aggregates, and their role in Alzheimer's disease is unclear, Anderton said. Additionally, he added, their lab and others have observed that there is an accumulation of insoluble proteins even during the normal aging process in the absence of disease. These insoluble proteins from older animals promote amyloid aggregation when mixed with amyloid beta in vitro.
The research team wondered what the relationship was between cumulative Alzheimer's disease and disease-free aging. They focused on amyloid beta protein and used a strain of the microscopic worm Caenorhabditis elegans, which has been used for years in aging research, that was genetically engineered to produce human amyloid protein.
Anderton said the research team suspects that amyloid beta causes some degree of insolubility in other proteins. “What we found is that amyloid beta causes a large amount of insolubility, even in very young animals,” Anderton said. They found that there is a subset of proteins that appear to be more susceptible to becoming insoluble, either by the addition of amyloid beta or by the normal aging process. They called that vulnerable subset the “core insoluble proteome.”
The researchers further demonstrated that the core insoluble proteome is enriched with proteins already associated with a variety of neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and prion diseases, in addition to Alzheimer's disease. did.
“Our paper shows that amyloid may play a role in promoting this normal aging aggregation,” Anderton said. “We think we now have, for the first time, clear evidence that both amyloid and aging have similar effects on the same proteins. It may be a vicious cycle where aging promotes insolubility and amyloid beta also promotes insolubility. is very high. And they only make each other worse.”
Amyloid protein is highly toxic to worms, and the research team wanted to find a way to reverse its toxicity. “Hundreds of mitochondrial proteins become insoluble both during aging and after the development of amyloid beta, so if we can use compounds to enhance the quality of mitochondrial proteins, we may be able to reverse some of the negative effects of amyloid beta. “I thought so,” Anderton said. That's exactly what they discovered using urolithin A, a natural intestinal metabolite produced when eating raspberries, walnuts, and pomegranates, which is known to improve mitochondrial function. Urolithin A significantly slows down the toxic effects of amyloid beta.
“What was clearly evident from our dataset is that the importance of mitochondria continues to emerge all the time,” Anderton said. The takeaway here, according to the authors, is that it's a reminder that mitochondrial health is crucial to overall health. “Mitochondria have a strong connection to aging. They also have a strong connection to amyloid beta,” he said. “We believe our study is one of the few to show that the insolubility and aggregation of these proteins may be at the link between the two.”
“Mitochondria are central to all of this, so one way to break the cycle of decline is to replace damaged mitochondria with new ones,” Lithgow said. “So how do you do it? Exercise and eat healthy.”
sauce:
Buck Aging Research Institute
Reference magazines:
Anderton, E., et al. (2024) Amyloid β accelerates age-related proteome-wide protein insolubility. Gero science. doi.org/10.1007/s11357-024-01169-1.
