A protein associated with the formation and maintenance of long-term memories has been shown to reverse age-related memory decline in fruit flies, offering a new explanation for why the brain gradually loses its ability to retain information. The findings, from a six-year study involving 10 million fruit flies, suggest that changes in the structure of beneficial amyloid proteins may contribute to memory deterioration as organisms age.
Published in the journal Cell, the research found that increasing production of a protein known as Funes improved memory in older flies, while increasing another protein with opposing functions damaged memory even in young individuals. The results point to a progressive shift in amyloid proteins from functional, beneficial forms towards more rigid and potentially harmful structures. Researchers say the mechanism could help explain some of the normal memory decline associated with ageing, although it remains to be established whether the same process occurs in humans.
The protein was named Funes after Funes the Memorious, the character created by Argentine writer Jorge Luis Borges in his short story about a young man who acquires an extraordinary ability to remember everything he has seen or experienced. Unable to forget, Funes declares: “More memories do I have by myself than all men have had since the world began.” The researchers chose the name for a protein involved in the biological processes that allow memories to persist.
Funes belongs to a large family of proteins called chaperones, which help other proteins fold into their correct three-dimensional structures. That shape is essential to their biological function. Properly folded proteins can perform their tasks, while incorrectly folded ones can trigger serious diseases, including prion encephalopathies such as bovine spongiform encephalopathy, commonly known as mad cow disease.
The research adds to a growing body of evidence challenging the conventional association between amyloid proteins and neurodegenerative disease. Amyloids are widely associated with conditions such as Alzheimer’s and Parkinson’s diseases, where abnormal protein accumulation can damage the brain. However, researchers have identified a different class of amyloids that perform essential biological functions. Unlike the harmful forms associated with dementia, these beneficial amyloids remain soluble rather than accumulating in damaging plaques. They help establish and maintain long-term memories.
In earlier research published in Science, the team detailed the first atomic-level structure of a beneficial amyloid protein, Orb2, demonstrating its essential role in memory formation and maintenance. The subsequent identification of other functional amyloids helped establish that the same broad category of proteins traditionally associated with neurodegeneration can also support normal biological processes.
The latest study examined how these proteins change throughout an organism’s life. Researchers spent six years studying the brains of fruit flies at eight different stages, from the first day after emerging from the egg to 35 days of age, corresponding to advanced old age. The scale of the undertaking involved approximately 10 million flies, with the researchers describing it as an unprecedented effort in this field.
By examining the proteins across multiple stages of life rather than taking a single snapshot, the team was able to trace changes in the molecular machinery responsible for memory. The experiments showed that increasing Funes production in older flies shifted their amyloid proteins towards more youthful states and improved their memory. In contrast, increasing the production of another chaperone, CG6693, which performs opposing functions, encouraged the accumulation of incorrectly folded amyloids and impaired memory, including in young flies.
Rubén Hervás, a Spanish biochemist who led the research, said the findings suggested a gradual transition towards protein structures resembling those associated with disease. “It is tempting to describe this as a transformation of the protein towards a more disease-like state, and there is some truth in that,” he told the researchers’ media interlocutor.
Hervás, who has spent about 20 years investigating beneficial amyloid proteins, leads a research group at the University of Hong Kong. His team collaborated on the study with Javier Oroz of the Blas Cabrera Institute of Physical Chemistry, part of Spain’s National Research Council (CSIC).
Hervás said the research had identified a previously unknown mechanism that could explain part of the reason memory deteriorates with age. The findings suggest that the biological systems supporting memory undergo gradual changes throughout life, eventually becoming less effective. “The machinery of memory is silently remodelled until it adopts a form that works less well,” he said.
The potential relevance to humans lies in the existence of proteins with similar functions. Orb2, the beneficial amyloid studied in fruit flies, has a human equivalent, including CPEB3. If the structural changes observed in Orb2 also occur in CPEB3 during human ageing, and if certain chaperones can reverse those changes, researchers may eventually be able to develop drugs that maintain or restore the protein’s functional state.
Hervás said such treatments could help preserve more efficient synaptic translation, the process associated with communication and connections between neurons, and improve memory. However, this possibility depends on establishing whether the molecular changes identified in fruit flies are also present in humans.
To investigate that question, Hervás has received a research grant worth one million euros from the Government of Hong Kong. The project will examine whether the mechanisms identified in the fruit-fly experiments are conserved in humans.
José Javier Lucas, a researcher at the Severo Ochoa Centre for Molecular Biology (CBM-CSIC), who was not involved in the study, described the findings as significant because they could help explain the molecular basis of memory loss that occurs with age. He said one of the major contributions of Hervás and his collaborators had been demonstrating that physiological amyloids can perform beneficial functions despite having structural characteristics traditionally associated with Alzheimer’s disease.
Lucas said the research represented “a whole change of paradigm in biology”, noting that amyloids regulate numerous physiological functions throughout the body, not only in the brain and memory. Their gradual loss of functionality could potentially explain other age-related problems, although the evidence remains incomplete. “It is not unreasonable that something like this could happen in humans, but we still have to demonstrate it,” he said.
