Brain discovery could improve drugs targeting amyloid diseases

Researchers at the Stowers Institute for Medical Research say they have identified how the brain deliberately forms amyloid proteins to turn fleeting experiences into long-term memories. 

The study provides the first direct evidence that the nervous system can intentionally form amyloids to store memories, challenging the long-held view that amyloids in the brain are harmful and opening up new possibilities for drug discovery.

“I wanted to understand how unstable proteins help create stable memories,” said Dr Kausik Si, Scientific Director at the Stowers Institute. “And now, we have definitive evidence that there are processes within the nervous system that can take a protein and make it form an amyloid at a very specific time, in a specific place and in response to a specific experience.”

Rethinking amyloids and disease

Amyloids are most associated with neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinson’s, where they form rigid protein fibres that damage neurons and erase memories. As a result, many drug development efforts have focused on preventing amyloid formation altogether.

The new research suggests this approach may be overly simplistic. The Stowers researchers demonstrated that amyloids can also be beneficial when their formation is tightly regulated, acting as stable molecular structures that help preserve memory.

“This expands the idea of a protein’s capacity to do meaningful things, and suggests there is an unknown universe of chaperone biology that we’ve long been missing,” Dr Si said.

Chaperones as molecular switches

The study focuses on specialised “chaperone proteins” in the fruit fly nervous system. While chaperones are typically thought to help proteins fold correctly or prevent harmful clumping, the researchers identified a previously unknown chaperone that instead enables a memory-related protein to assemble into a functional amyloid.

The findings build on a 2020 study from the Si Lab showing that amyloid formation is required for long-term memory, but until now the mechanism controlling that process had been unknown.

“The fact that amyloid is needed to form memory implied there must be a mechanism that controls the process,” said Dr Rubén Hervas, co-corresponding author of the study.

Discovering Funes

By manipulating 30 different chaperones in fruit flies, the team identified a key regulator which they named Funes.

“We were inspired by Jorge Luis Borges’ short story Funes the Memorious in which one man’s perfect memory comes at a cost, so we named the chaperone Funes,” said lead author Dr Kyle Patton.

Fruit flies with increased levels of Funes showed strong long-term memory, while engineered versions of the protein that could not trigger amyloid formation caused memory to fail entirely.

Implications for drug discovery

Beyond memory research, the findings may have implications for treating brain disorders. Rather than blocking amyloids indiscriminately, future drugs could aim to target the chaperones that regulate amyloid formation, fine-tuning the process instead of shutting it down.

“Discovering this chaperone protein has now provided us with an avenue to potentially approach amyloid-based diseases in an unanticipated way,” Dr Si said. “It may be possible to either activate these chaperones and guide toxic amyloids to be less harmful.”

The researchers believe similar mechanisms may operate in vertebrate brains. “Our hypothesis is carrying us all the way to the vertebrate brain, illustrating that it may actually be universal,” Dr Si said.

Unexpectedly, some of the chaperone genes studied have also been linked to schizophrenia in human genetic studies, suggesting wider relevance to brain health.