Save the "disappeared her" in your mind! Can protein modification help you "remember"?

◎Reporter Zhang Jiaxin

Improving memory is an eternal topic of concern to us. As people age, their memory declines, which is a natural physiological law. At the same time, some diseases, such as Alzheimer's disease, have a common symptom of memory loss. Is there any way to improve people's memory?

Recently, a paper published in the journal Science Advances stated that neuroscientists have designed a synthetic protein that can promote memory function in elderly people with cognitive decline. They genetically modified the LIMK1 protein and embedded a synthetic peptide "molecular switch" that can be activated under the action of immunosuppressive drugs and significantly improve the memory of experimental animals. This discovery brings hope to patients with Alzheimer's disease and other neurodegenerative diseases and is expected to "revolutionize the field of neurology."

How is memory formed? How does the synthetic peptide "molecular switch" work ? Around these questions, Science and Technology Daily interviewed the first author of the paper, Christian Ripoli, associate professor of physiology at the Catholic University of the Sacred Heart in Italy, and the senior author of the paper, Claudio Grassi, director of the Department of Neuroscience at the Catholic University of the Sacred Heart School of Medicine, and professor of physiology and psychology.

Memory is a complex process

"Memory is a complex process that involves changes in the synapses that connect neurons in specific areas of the brain, such as the hippocampus. This phenomenon of synaptic changes is called synaptic plasticity," said Grassi.
In an interview, Ripoli introduced the process of memory formation to reporters: "Memory is usually understood as explicit memory. And explicit memory includes information about places, people and objects. Clinical evidence and preclinical studies on mammals have identified key brain areas involved in signal processing and memory formation, including the hippocampus and related areas of the medial temporal lobe."

In the neural circuits of these brain regions, synapses transmit information through electrical signals. These transmissions lead to protein modifications, activation or inactivation, and changes in protein expression, which in turn trigger long-term changes in the strength of synaptic connections. These protein changes enable a person to recall the activation of the same neurons at certain moments, thus helping to preserve and retrieve memories over time.

So how do memories strengthen and weaken? Ripoli says it has to do with LTP.

Long-term synaptic plasticity refers to the response of neuronal synapses to long-term stimulation. LTP is an important type of long-term synaptic plasticity, which means that under certain stimulation conditions, the synaptic efficacy between neurons can be enhanced for a long time. Dendritic spines are the main site for synapses between neurons. And LTP occurs on dendritic spines. On dendritic spines, hundreds of proteins can change their functions during LTP.

Dendritic spines enhance information transmission in neural networks and are essential for learning and memory processes. Memory is mediated through this plasticity.

LIMK1 is closely related to memory

Unless affected by LTP, dendritic spines maintain a relatively stable structure, Ripoli said. The maintenance of the structure depends on the opposing activities of two proteins, cofilin and actin. Actin naturally tends to polymerize, while cofilin cuts actin polymers, creating a balance.

At this point, the LIMK1 protein comes into play. "The LIMK1 protein is a kinase, a protein that binds adenosine triphosphate (ATP) and phosphorylates its targets," Ripoli said. "The LIMK1 protein plays a crucial role in determining the structural changes of neurons, namely the formation of dendritic spines."
The LIMK1 protein phosphorylates cofilin and inhibits it, allowing actin to polymerize and enlarge dendritic spines. By increasing the size of dendritic spines, neurons are more likely to communicate.
"In fact, in Alzheimer's disease, the number and volume of dendritic spines are reduced," said Ripoli.

This time, the research team's goal is to regulate the activity of the LIMK1 protein. Controlling the LIMK1 protein with drugs means that synaptic plasticity can be promoted, thereby regulating memory.

The research team designed the LIMK1 protein, introduced a synthetic peptide "molecular switch" into it, and controlled the "molecular switch" with rapamycin.

Ripoli said that the site where LIMK1 protein binds to ATP is close to the "molecular switch", and without rapamycin, the synthetic peptide "molecular switch" will remain closed. With rapamycin, the synthetic peptide "molecular switch" will be turned on, thereby reactivating the LIMK1 protein.
Ripoli further introduced that rapamycin is a drug known for its ability to cross the blood-brain barrier and has been approved by the U.S. Food and Drug Administration (FDA). Studies have shown that it can extend lifespan and enhance cognitive ability. Therefore, rapamycin may work synergistically with the LIMK1 protein designed by researchers to potentially slow or reverse cognitive impairment observed in experimental models of various neurological and psychiatric diseases.

Whether it can be used in humans needs further verification

"The engineered LIMK1 protein enhanced memory in mice by increasing dendritic spine volume and neural communication in the hippocampus," Ripoli said. "The improvement was so dramatic in older mice with cognitive deficits that they showed signs of improved memory in tests such as novel object recognition and identification of object locations."

This approach allows researchers to manipulate synaptic plasticity processes and memory under both physiological and pathological conditions. In addition, Grassi emphasizes that it paves the way for the development of further engineered proteins that could revolutionize research and treatment in the field of neurology.

Grassi said that next, they will verify the effectiveness of this treatment in experimental models of neurodegenerative diseases that show memory deficits, such as Alzheimer's disease. Of course, more research is needed to confirm whether this method can be safely and effectively applied to humans.