UCLA researchers have discovered a molecule, DDL-920, that restores cognitive function in mice with Alzheimer’s disease by enhancing gamma oscillations in the brain, a potential breakthrough in therapeutic methodology beyond current drug-based plaque removal strategies.
UCLA researchers suggest that a compound could improve the brain’s electrical rhythms and treat schizophrenia and depression, pending human clinical trials.
In a recent study, researchers at UCLA Health identified and synthesized a molecule that restores cognitive function in mice exhibiting cognitive impairment. Alzheimer’s Disease “Reactivating memory circuits in the brain reduces the symptoms of Alzheimer’s. If the compound has a similar effect in humans, it could represent a breakthrough Alzheimer’s treatment with a unique ability to restore memory and cognition,” the study authors say.
“There is nothing like this on the market, and nothing that has been empirically proven to have this effect,” said Dr. Istvan Modi, lead author of the study and professor of neurology and physiology. University of California, Los Angeles health.
The molecule, DDL-920, works differently from recently FDA-approved Alzheimer’s drugs, such as lecanemab and aducanumab, which remove harmful plaques that build up in the brains of Alzheimer’s patients and have been shown to slow the rate of cognitive decline, but does not restore memory or cognitive impairment.
“It may not leave plaques in the brain, but all the pathological changes in neural circuits and mechanisms will not be corrected,” Modi said.
Study details and results
In the study, published in the Proceedings of the National Academy of Sciences, UCLA researchers led by Dr. Istvan Modi and Dr. Varghese John, professor of neurology and director of the Drug Discovery Laboratory (DDL) at the Mary S. Easton Alzheimer’s Disease Research and Care Center, set out to find a compound that could figuratively switch the brain’s memory circuits back on.
Like a traffic light, the brain fires electrical signals at different rhythms to start and stop various functions. Gamma oscillations are among the highest frequency rhythms and have been shown to regulate brain circuits underlying cognitive processes and working memory (the type of memory used to remember phone numbers). Patients with early symptoms of Alzheimer’s, such as mild cognitive impairment, have been found to have reduced gamma oscillations, Modi said.
Other studies have used neuromodulation techniques to stimulate gamma waves to restore memory: Auditory, visual and transcranial magnetic stimulation at 40 hertz (Hz), the frequency that makes a cat purr, was effective in dissolving plaque in the brain, but again, no significant cognitive improvements were seen, Modi said.
In this latest study, Modi and his team tried to approach the problem from a different angle: Even if it’s not possible to activate these memory circuits using external tools, there may be a way to stimulate these electrical rhythms from the inside, using molecules.
Specifically, they wanted a compound that would target certain fast-firing neurons called paravalbumin interneurons, which are important for generating gamma oscillations and, therefore, memory and cognitive function. But certain chemical receptors on these neurons that respond to a chemical messenger called GABA act like a brake pedal, dampening the gamma oscillations caused by these neurons.
Modi, John and their team identified a compound, DDL-920, that antagonizes these receptors, allowing neurons to sustain stronger gamma oscillations.
To test whether this actually translates into improved memory and cognition, the researchers used mice that were genetically engineered to have symptoms of Alzheimer’s disease.
Both Alzheimer’s disease model mice and wild-type mice underwent baseline cognitive testing in the Barnes maze, a circular platform surrounded by visual cues and containing a single escape exit. The maze is used to measure how well rodents can learn and remember the location of the escape exit.
Experimental Results
Following initial testing, the researchers administered DDL-920 orally twice daily for two weeks to mice modeling Alzheimer’s disease. After treatment, the mice were able to recall the escape route in a maze just as quickly as wild-type mice. What’s more, the treated mice showed no abnormal behavior, hyperactivity, or other visible side effects over the two weeks.
Modi said that while the treatment was effective in mice, more research is needed to determine whether it is safe and effective in humans. If ultimately proven effective, the drug could have implications for treating other diseases and health conditions in which gamma oscillations are reduced, such as depression, schizophrenia and depression. Autism spectrum disorderModi said.
“We are very enthusiastic about this research as it is novel and the mechanism of action has not been addressed before,” Modi said.
Reference: “Therapeutic small molecules enhance gamma oscillations and improve cognition/memory in Alzheimer’s disease model mice,” Xiaofei Wei, Jesus J. Campagna, Barbara Jagodzinska, Dongwook Wi, Whitaker Cohn, Jessica T. Lee, Chunni Zhu, Christine S. Huang, László Molnár, Carolyn R. Houser, Varghese John, Istvan Mody, August 6, 2024, Proceedings of the National Academy of Sciences of the United States of America.
Translation: 10.1073/pnas.2400420121
