Breaking the vicious cycle of protein clumping in Alzheimer’s

Buck Institute research highlights intricate interplay of insoluble proteins in neurodegenerative diseases and aging.

One of the hallmark features of Alzheimer’s disease, alongside other neurodegenerative disorders, is the accumulation of insoluble protein aggregates in the brain. However, the process of aging still results in a gradual buildup of these insoluble proteins, even in the absence of disease.

Now researchers at the Buck Institute for research on aging have embarked on a groundbreaking study exploring the connections between insoluble proteins in neurodegenerative diseases like Alzheimer’s and the aging process itself, shedding light on potential interventions to disrupt this cycle.

Longevity.Technology: Despite decades of intensive research, effective therapies for Alzheimer’s disease are still elusive, and the global burden of this condition continues to escalate. With Alzheimer’s disease treatment clinical trial at a depressing 98% failure rate, it is time to innovate – instead of fixating solely on individual proteins, the field must embrace a more holistic view, as the Buck has done, considering protein insolubility as a general phenomenon. This shift in perspective could pave the way for novel therapeutic strategies capable of addressing the multifaceted nature of Alzheimer’s disease and aging-related neurodegeneration.

The recent study conducted by Buck researchers in the microscopic worm Caenorhabditis elegans offers a fresh perspective on neurodegeneration. By engineering worms to produce human amyloid protein, the researchers uncovered a complex network of interactions between insoluble proteins, suggesting a common underlying mechanism in neurodegenerative diseases and aging. The study’s findings not only challenge the prevailing protein-by-protein paradigm but also underscore the significance of mitochondrial health in combating neurodegenerative diseases [1].

“Based on our discoveries, targeting insoluble proteins could provide a strategy for the prevention and treatment of a variety of age-related diseases,” said Edward Anderton, PhD, a postdoctoral fellow in Gordon Lithgow’s lab and co-first author of the study published yesterday in the journal GeroScience.

“Our study shows how maintaining healthy mitochondria can combat protein clumping linked to both aging and Alzheimer’s,” said Manish Chamoli, PhD, a research scientist in Gordon Lithgow’s and Julie Andersen’s lab, and co-first author of the study. “By boosting mitochondrial health, we can potentially slow down or reverse these harmful effects, offering new ways to treat both aging and age-related diseases.”

L-R: Edward Anderton, Manish Chamoli and Gordon Lithgow

The geroscience hypothesis

The strong correlation between insoluble proteins fostering normal aging and diseases also supports the broader understanding of the mechanisms underlying aging and age-related diseases.

“We would argue that this work really supports the geroscience hypothesis that there is a common pathway to Alzheimer’s disease and aging itself,” said Buck Professor Gordon Lithgow, PhD, Vice President of Academic Affairs and the senior author of the study. “Aging is driving the disease, but the factors that put you on the track toward the disease actually occur very early.”

The discovery by the Buck team of a core insoluble proteome packed with numerous – and previously unconsidered – proteins presents novel targets for investigation.

“In some ways it raises the flag about whether we should be thinking about what Alzheimer’s looks like in very young people,” said Lithgow.

A broader outlook

The predominant focus of Alzheimer’s disease research has centered on addressing the buildup of two headline-grabbing proteins: amyloid beta and tau. However, Anderson pointed out that there are actually thousands of other proteins in these insoluble aggregations, and their role in Alzheimer’s disease is unknown. Furthermore, he noted observations from their lab and others indicating that even in the absence of disease, the normal aging process is accompanied by the accumulation of insoluble proteins. Notably, when these insoluble proteins from aged animals were combined with amyloid beta in vitro, they expedited the aggregation of amyloid.

This led the researchers to question connection between the accumulation aggregates seen in Alzheimer’s and disease-free aging. Enter the longevity researcher’s friend – the nematode C elegans; the Buck team used a strain of the microscopic worm that had been engineered to produce human amyloid protein, and Anderton explained that the researchers suspected they might see that amyloid beta is driving some level of insolubility in other proteins.

“What we found is that amyloid beta causes a massive amount of insolubility, even in a very young animal,” said Anderton. The researchers discovered that there is a subset of proteins that seem to be particularly vulnerable to becoming insoluble, either by adding amyloid beta or during the normal aging process. They termed that vulnerable subset the core insoluble proteome.

The team showed that the central insoluble proteome harbors proteins previously associated with various neurodegenerative conditions; these extend beyond Alzheimer’s to encompass Parkinson’s disease, Huntington’s disease and prion disease.

“Our paper shows that amyloid could be acting as a driver of this normal aging aggregation,” said Anderton. “Now we’ve got clear evidence, I think for the first time, that both amyloid and aging are affecting the same proteins in a similar way. It’s quite possibly a vicious cycle where aging is driving insolubility and amyloid beta is also driving insolubility, and they’re just making each other worse.”

The amyloid protein exhibits significant toxicity to the worms, prompting the team to seek methods to counteract this harmful effect.

“Since hundreds of mitochondrial proteins become insoluble both during aging and after expressing amyloid beta, we thought if we can boost the mitochondrial protein quality using a compound, then maybe we can reverse some of the negative effects of amyloid beta,” said Anderton.

And that’s what they did; the researchers discovered that urolithin A, a natural gut metabolite found in foods like raspberries, walnuts and pomegranates, and known for its ability to enhance mitochondrial function, notably attenuated the toxic effects of amyloid beta.

“Something that was glaringly obvious from our dataset is that the importance of mitochondria keeps coming up,” said Anderton. The paper authors say this is a key take away from the research – that it should not be forgotten that the health of mitochondria is critical to overall health.

“Mitochondria have a strong link with aging,” explained Anderton. “They’ve got a strong link with amyloid beta. I think ours is one of the few studies that shows that insolubility and aggregation of those proteins might be the link between the two.”

“Because the mitochondria are so central to all of this, one way to break the vicious cycle of decline is to replace damaged mitochondria with new mitochondria,” said Lithgow. “And how do you do that? You exercise and follow a healthy diet.”

Photographs courtesy of the Buck Institute