The aggregation of insoluble proteins in the brain is a well-established hallmark of Alzheimer’s disease and various other neurodegenerative conditions, as well as a natural consequence of ageing. While traditional approaches to treating Alzheimer’s have typically focused on targeting individual insoluble proteins like amyloid beta or tau, a recent study by researchers at Buck Institute has illuminated broader implications. They conducted a comprehensive investigation using Caenorhabditis elegans, a model organism, to explore the intricate interplay between insoluble proteins in neurodegenerative diseases and ageing.

Edward Anderton, PhD, a postdoctoral fellow at Gordon Lithgow’s lab and co-first author of the study, highlighted their findings suggesting that interventions targeting insoluble proteins could hold promise for treating age-related diseases. The research underscored a crucial intervention: enhancing mitochondrial health to counteract the toxic effects of protein aggregates. By bolstering mitochondrial function, they observed a potential to mitigate or reverse the harmful consequences of protein clumping associated with ageing and diseases like Alzheimer’s.

Their work supports the geroscience hypothesis, which posits common underlying pathways in ageing and age-related diseases and identifies a core insoluble proteome enriched with proteins previously overlooked in disease research. This discovery opens new avenues for therapeutic exploration, challenging the conventional focus on amyloid beta and tau. Gordon Lithgow, PhD, Vice President of Academic Affairs at Buck Institute, stressed the broader implications, suggesting that understanding these proteins’ role in ageing could reshape how we approach Alzheimer’s disease, possibly even in younger populations.

Beyond amyloid beta and tau, which have dominated Alzheimer’s research, the study revealed that numerous other proteins contribute to insoluble aggregations, influencing disease progression and ageing processes. The researchers found that amyloid beta exacerbates protein insolubility during ageing and triggers a cascade effect, accelerating aggregation across a vulnerable subset of proteins termed the “core insoluble proteome.” This subset includes proteins implicated in various neurodegenerative diseases beyond Alzheimer’s, such as Parkinson’s and Huntington’s diseases.

The team’s experiments yielded promising results with Urolithin A, a compound derived from foods like raspberries, walnuts, and pomegranates known for enhancing mitochondrial function. It significantly delayed the toxic effects of amyloid beta in their model system, suggesting a potential therapeutic strategy to mitigate protein aggregation’s detrimental effects. This approach highlights mitochondria’s pivotal role in maintaining cellular health and its potential as a target for interventions to break the decline cycle associated with ageing and neurodegeneration.

In conclusion, the study by Buck researchers sheds light on the complex relationship between insoluble proteins, ageing, and neurodegenerative diseases. It challenges existing paradigms by broadening our understanding of protein aggregation beyond amyloid beta and tau, proposing mitochondria as a critical nexus. By targeting insoluble proteins and enhancing mitochondrial health, the study presents new opportunities to intervene in Alzheimer’s disease and other age-related conditions. This could potentially pave the way for innovative therapeutic strategies focused on enhancing overall mitochondrial function through lifestyle modifications like exercise and diet, instilling optimism about the future of Alzheimer’s research and treatment.

More information: Edward Anderton et al, Amyloid β accelerates age-related proteome-wide protein insolubility, GeroScience. DOI: 10.1007/s11357-024-01169-1

Journal information: GeroScience Provided by Buck Institute for Research on Aging