Summary: A new study in worms reveals a set of insoluble proteins linked to both aging and Alzheimer’s disease. These proteins accumulate during normal aging and are exacerbated by beta-amyloid, a hallmark of Alzheimer’s disease. Boosting mitochondrial health with a natural compound reversed the toxic effects of protein clumping, highlighting the importance of mitochondria in fighting age-related diseases.
Highlights:
- A set of insoluble proteins is linked to both aging and Alzheimer’s disease.
- Beta-amyloid exacerbates protein clumping, creating a vicious cycle of decline.
- Improving mitochondrial health can reverse the toxic effects of protein clumping.
Source: Buck Institute
It has long been known that Alzheimer’s disease, like most other neurodegenerative diseases, is characterized by the clumping of insoluble protein aggregates in the brain. During normal disease-free aging, there is also an accumulation of insoluble proteins.
To date, therapeutic approaches to Alzheimer’s disease have not addressed the contribution of protein insolubility as a general phenomenon, focusing instead on one or two insoluble proteins.
Buck researchers recently completed a systematic study of worms that paints a complex picture of the links between insoluble proteins in neurodegenerative diseases and aging.
Additionally, the work demonstrated an intervention that could reverse the toxic effects of aggregates by improving mitochondrial health.
“Based on our findings, targeting insoluble proteins could provide a strategy for prevention and treatment of various age-related diseases,” said Edward Anderton, PhD, a postdoctoral researcher in Gordon Lithgow’s laboratory and co-first author from a study which appears in the May 16 issue of the journal GeroScience.
“Our study shows how maintaining healthy mitochondria can combat protein clumping linked to both aging and Alzheimer’s disease,” said Manish Chamoli, PhD, a research scientist in Gordon Lithgow and Julie’s lab. Andersen, and co-first author of the study.
“By improving mitochondrial health, we can potentially slow or reverse these harmful effects, providing new ways to treat both aging and age-related diseases.” »
Results support the geroscience hypothesis
The close link between insoluble proteins promoting normal aging and disease also argues for a broader view of how aging and age-related diseases occur. “We would say that this work really supports the geroscientific hypothesis that there is a common pathway leading to Alzheimer’s disease and to aging itself,” said Professor Buck Gordon Lithgow. PhD, vice president for academic affairs and lead author of the study.
“Aging drives disease, but the factors that put you on the path to disease actually occur very early. »
The fact that the team found a core insoluble proteome enriched with many proteins that had not been previously considered creates new targets for exploration, Lithgow said. “In some ways it raises the question of whether we should be thinking about what Alzheimer’s disease looks like in the very young,” he said.
Beyond Amyloid and Tau
Until now, most research into Alzheimer’s disease has targeted accumulations of two proteins: beta-amyloid and tau. But there are actually thousands of other proteins in these insoluble aggregates, Anderton said, and their role in Alzheimer’s disease was unknown.
Additionally, he added, their lab and others observed that during the normal process of disease-free aging, there was also a buildup of insoluble proteins. These insoluble proteins from aged animals, when mixed with amyloid beta in the test tube, accelerate the aggregation of the amyloid.
What was the link between the accumulation of Alzheimer’s disease aggregates and disease-free aging, the team wondered. Focusing on the beta-amyloid protein, they used a strain of the microscopic worm Caenorhabditis elegans, long used in studies of aging, which was designed to produce human amyloid protein.
Anderton said the team suspected they might see that beta-amyloid caused some level of insolubility in other proteins.
“What we found is that beta-amyloid causes massive insolubility, even in a very young animal,” Anderton said. They found that there is a subset of proteins that appear very vulnerable to becoming insoluble, either by adding beta-amyloid or during the normal aging process. They called this vulnerable subset the “core insoluble proteome.”
The team then demonstrated that the core insoluble proteome is full of proteins already associated with different neurodegenerative diseases in addition to Alzheimer’s disease, including Parkinson’s disease, Huntington’s disease and prion disease.
“Our paper shows that amyloid could act as a driver of this aggregation in normal aging,” Anderton said.
“Now we have clear evidence, I think for the first time, that amyloid and aging affect the same proteins in the same way. This is most likely a vicious cycle in which aging causes insolubility and beta-amyloid also causes insolubility, and they only make each other worse.
Amyloid protein is very toxic to worms and the team wanted to find a way to reverse this toxicity.
“Since hundreds of mitochondrial proteins become insoluble both during aging and after expressing beta-amyloid, we thought that if we could improve the quality of mitochondrial proteins using a compound, we “We might be able to reverse some of the negative effects of beta-amyloid,” Anderton said.
That’s exactly what they found, using urolithin A, a natural intestinal metabolite produced when we eat raspberries, walnuts and pomegranates, known to improve mitochondrial function: it significantly delayed the toxic effects of beta-amyloid.
“What’s clear from our data set is that the importance of mitochondria continues to emerge,” Anderton said. The takeaway, the authors say, is to remember that mitochondrial health is essential to overall health.
“Mitochondria have a strong link to aging. They have a strong connection with beta-amyloid,” he said. “I think ours is one of the few studies that shows that the insolubility and aggregation of these proteins could be the link between the two.”
“With mitochondria at the heart of it all, one way to break the vicious cycle of decline is to replace damaged mitochondria with new mitochondria,” Lithgow said. “And how do you do that? You exercise and eat a healthy diet.
Other Buck researchers involved in the study include Dipa Bhaumik, Christina D. King, Xueshu Xie, Anna Foulger, Julie K. Andersen and Birgit Schilling.
Funding: This work was supported in part by funds from the National Institute on Aging (NIA RF1AG057358 NIA U01AG045844), a shared instrumentation grant from the National Institutes of Health, and the Larry L. Hillblom Medical Foundation.
About this news on Alzheimer’s research, genetics and aging
Author: Kris Rébillot
Source: Beck Institute
Contact: Kris Rebillot – Beck Institute
Picture: Image is credited to Neuroscience News
Original research: Free access.
“Amyloid β accelerates age-related proteome-wide protein insolubility” by Edward Anderton et al. GeroScience
Abstract
Amyloid β accelerates age-related proteome-wide protein insolubility
Loss of proteostasis is a highly conserved feature of aging in model organisms and results in the accumulation of insoluble protein aggregates.
Protein insolubility is also a unifying feature of major age-related neurodegenerative diseases, including Alzheimer’s disease (AD), in which hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques.
Despite the link between aging and AD risk, therapeutic approaches to date have overlooked widespread aging-induced protein insolubility as a contributing factor. However, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro and lifespan in vivo.
Here, using an unbiased proteomic approach, we questioned the relationship between Aβ and age-related protein insolubility.
Specifically, we found that Aβ expression drives proteome-wide protein insolubility in C. eleganseven in young animals, and this insoluble proteome is very similar to the insoluble proteome driven by normal aging, this vulnerable subproteome we call the core insoluble proteome (CIP).
We show that CIP is enriched with proteins that modify Aβ toxicity in vivo, suggesting the possibility of a vicious feedback cycle in the context of AD.
Importantly, using human genome-wide association studies (GWAS), we show that CIP is teeming with biological processes involved not only in neurodegenerative diseases, but also in a wide range of related chronic diseases. to age (CARD).
This provides evidence suggesting that age-related loss of proteostasis may play a role in overall CARD risk.
Finally, we show that urolithin A, a gut-derived geroprotective metabolite, alleviates Aβ toxicity, supporting its use in clinical trials for dementia and age-related diseases.
News Source : neurosciencenews.com
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