A new study in fruit flies has shown that a protein called Funes can restore age-related memory loss, and that another chaperone with opposite functions impairs memory in young individuals. The work, published in Cell, suggests that memory loss may be tied to a gradual shift of amyloid proteins from a beneficial form to a harmful one, and offers a potential explanation for normal memory decline in aging.
The study, led by biochemist Rubén Hervás at the University of Hong Kong in collaboration with the team led by Javier Oroz at the Blas Cabrera Institute of Physical Chemistry of Spain's National Research Council (CSIC), involved six years of work examining the brains of 10 million fruit flies at eight life stages, from the first day after hatching to 35 days of age, the equivalent of old age in humans.
The researchers focused on the Funes protein, a chaperone that helps fold proteins into their functional three-dimensional shape. It is named after the Jorge Luis Borges story "Funes the Memorious," about a young man with a perfect memory. The Funes protein is closely related to amyloids, a class of proteins typically associated with degenerative diseases like Alzheimer's. Unlike disease-related amyloids, however, these do not accumulate as harmful plaques but remain soluble and play a beneficial role in forming and maintaining memories.
When the researchers increased production of the Funes protein in aged flies, they observed that the amyloids reverted to more rejuvenated states and memory improved. Conversely, when they increased production of a chaperone with opposite functions, CG6693, even young flies accumulated misfolded amyloids and had worse memory.
"It is tempting to describe this as a transformation of the protein toward a state more similar to disease, and there is some truth in that," said Hervás, who has spent about 20 years exploring beneficial amyloid proteins. He believes the work "uncovers a new mechanism that may explain part of why memory is lost with age."
The study builds on a discovery published in January, in which scientists described the first atomic-level structure of Orb2, an amyloid protein that plays a role in forming and maintaining memories in flies. Since then, several such beneficial amyloids have been identified. The beneficial amyloids in flies, Orb2, have equivalents in humans, including CPEB3.
Hervás noted that by examining the entire process across the lifespan, researchers were able to observe how "the machinery of memory is silently remodelled until it adopts a form that functions less effectively."
"If what we found in flies is conserved in humans — that is, if CPEB3 undergoes structural changes during aging similar to those of Orb2 and certain chaperones can reverse them — in principle drugs could be developed to maintain or restore CPEB3 to more functional states, associated with more efficient synaptic translation and better memory," Hervás said. He has received a €1 million (about $1.12 million) grant from the Hong Kong government to determine whether the same process occurs in humans.
José Javier Lucas, a researcher at the Severo Ochoa Molecular Biology Centre (CBM-CSIC) who was not involved in the study, said the work "could be part of the explanation for something previously unknown: the molecular keys to the memory loss everyone experiences with age." He highlighted the achievement of demonstrating "physiological" amyloids that perform beneficial functions despite their structure traditionally associated with Alzheimer's disease. Lucas called the study "a complete paradigm shift in biology," noting that amyloids regulate many physiological functions and that their gradual loss of functionality may explain many age-associated problems. He added, "It is not far-fetched to think that something like this could occur in a human, but we still have to demonstrate it."
Analysis
Why This Matters
- Identifies a potential molecular mechanism behind normal age-related memory loss, which has remained largely unknown.
- Shows that memory impairment in aged flies is reversible by boosting a beneficial protein, raising the prospect of future treatments for humans that target the same pathway.
- The work challenges the long-held view that all amyloid proteins are harmful, suggesting some are essential for memory and may be central to aging.
Background
The human brain reaches peak capacity before age 30, after which some abilities slowly decline. Much more is known about how memories are formed than how they are lost. Memory decline is usually attributed to brain shrinkage and loss of neuronal connections, but the molecular basis has been unclear. Amyloids were first identified in association with Alzheimer's disease and other neurodegenerative conditions, but recent studies have found that some amyloids play beneficial roles, including in memory. The Funes protein is a chaperone that helps maintain the correct shape of proteins.
Key Perspectives
- Rubén Hervás (lead author, University of Hong Kong): Says the study "uncovers a new mechanism that may explain part of why memory is lost with age." He notes that if the findings are conserved in humans, drugs could potentially restore memory by targeting the protein CPEB3. He has received a €1 million grant to test this in humans.
- José Javier Lucas (CBM-CSIC, not involved in the study): Describes the work as "a complete paradigm shift in biology," highlighting that it demonstrates "physiological" amyloids with beneficial functions. He says it is not far-fetched that a similar process could occur in humans but warns it still needs to be demonstrated.
What to Watch
- Whether the findings in flies are replicated in human cells or animal models closer to humans.
- Results from the Hong Kong government-funded study led by Hervás to determine if CPEB3 undergoes similar structural changes in humans.
- Any pharmaceutical interest in developing drugs that maintain or restore the beneficial form of human CPEB3.
Checked
12 claims in this story checked against 1 source: 12 supported.
Show each claim
- SupportedThe study suggests age-related memory loss may be reversible in flies; the opening says Funes restored memory in aged flies.El País English: “Now, a new study has shown that the Funes protein can restore memory in old age... The work was done in fruit flies”
- SupportedIncreasing the opposite-function chaperone CG6693 impaired memory in young flies.El País English: “when they increased production of another chaperone with opposite functions — CG6693 — they observed that even young flies accumulated misfolded amyloids and had worse memory.”
- SupportedThe study suggests memory loss may be related to a gradual shift of amyloid proteins from a functional, benign form to a harmful state.El País English: “The study, published in Cell, suggests that memory loss may be related to a progressive transition of amyloid proteins from their functional, benign form to a more rigid, harmful state.”
- SupportedThe work involved six years of research on 10 million fruit flies at eight life stages, from the first day after hatching to 35 days old.El País English: “The researchers spent six years studying the tiny brains of 10 million fruit flies at eight stages of their lives, from the first day after hatching to 35 days of age”
- SupportedRubén Hervás led the study and collaborated with Javier Oroz’s team at the Blas Cabrera Institute of Physical Chemistry of Spain’s CSIC.El País English: “Rubén Hervás, the Spanish biochemist who led the study... collaborated on the project with the team led by Javier Oroz at the Blas Cabrera Institute of Physical Chemistry of Spain’s National Research Council (CSIC).”
- SupportedHervás said, “It is tempting to describe this as a transformation of the protein toward a state more similar to disease, and there is some truth in that.”El País English: ““It is tempting to describe this as a transformation of the protein toward a state more similar to disease, and there is some truth in that,” says Rubén Hervás”
- SupportedHervás said the work “uncovers a new mechanism that may explain part of why memory is lost with age.”El País English: “Hervás believes this work... “uncovers a new mechanism that may explain part of why memory is lost with age.””
- SupportedHervás said the “machinery of memory is silently remodelled until it adopts a form that functions less effectively.”El País English: “researchers were able to observe how “the machinery of memory is silently remodelled until it adopts a form that functions less effectively.””
- SupportedHervás said that if the fly findings are conserved in humans, drugs could in principle be developed to restore CPEB3 to more functional states and improve memory.El País English: ““If what we found in flies is conserved in humans — that is, if CPEB3 undergoes structural changes during aging similar to those of Orb2 and certain chaperones can reverse them — in principle drugs could be developed to maintain or restore CPEB3 to more functional states”
- SupportedHervás received a €1 million grant from the Hong Kong government to investigate whether the process also occurs in humans.El País English: “The scientist has received a €1 million ($1.12 million) grant from the Hong Kong government to determine whether what they have just discovered in flies also occurs in humans.”
- SupportedLucas said the work “could be part of the explanation” for the molecular basis of age-related memory loss.El País English: ““Something like this could be part of the explanation for something previously unknown: the molecular keys to the memory loss everyone experiences with age,” he says.”
- SupportedLucas called the study “a complete paradigm shift in biology.”El País English: “Lucas believes the study represents “a complete paradigm shift in biology.””
