Molecule restores cognitive function and memory in Alzheimer's disease model mice

If proven effective in humans, the study authors said the candidate compound would represent a novel treatment for Alzheimer's disease in its ability to restore memory and cognition.

“There's really nothing on the market or ly proven to have this effect,” said Dr. Istvan Modi, a professor of neurology and physiology at UCLA Health and lead author of the study.

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.

In a study published in the journal Proceedings of the National Academy of SciencesResearchers led by UCLA's Istvan Modi, PhD, and Varghese John, PhD, professor of neurology and director of the Drug Discovery Lab 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, 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, which is used to measure how well rodents can learn and remember the location of the escape exit.

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's safe and effective in humans. If ultimately proven effective, Modi said the drug could have implications for treating other diseases and health conditions where gamma oscillations are reduced, including depression, schizophrenia and autism spectrum disorder.

“We are very enthusiastic about this research as it is novel and the mechanism of action has not been addressed before,” Modi said.