New research has shown that a molecule identified and synthesized by UCLA Health researchers restores cognitive functions in mice with symptoms of Alzheimer’s disease by effectively reactivating the brain’s memory circuits. If its effects are proven to be similar in humans, the compound could become a new Alzheimer’s treatment candidate for its ability to revitalize memory and cognition, the study’s authors said.
“There’s really nothing like this on the market or experimentally that has been shown to do this,” said Dr. Istvan Mody, a professor of neurology and physiology at UCLA Health and senior author of the study, which was published in the journal The Proceedings of the National Academy of Sciences.
The DDL-920 molecule works differently than recently FDA-approved drugs for Alzheimer’s disease, such as lecanemab and aducanumab, which remove toxic plaque that builds up in the brains of patients with this type of dementia. Although removing this plaque has been shown to slow cognitive decline, it does not restore memory or reverse cognitive deficits.
“They leave behind a brain that may not have plaques, but not all of the pathological alterations in the circuitry and mechanisms of neurons are corrected,” said Mody, who led the UCLA team of researchers with Dr. Varghese John, professor of neurology and director of the Drug Discovery Laboratory (DDL) at the Mary S. Easton Center for Alzheimer’s Disease Research and Care.
Reactivate memory circuits in the brain
The goal of these scientists was to find a compound that would flip the switch back on in the brain’s memory circuits. Similar to a traffic signal, the brain sends out electrical signals at different rates to start and stop various functions. Gamma oscillations are some of the highest-frequency rhythms and have been shown to orchestrate brain circuits underlying cognitive processes and working memory (the type of memory used to remember a phone number). Patients with early symptoms of Alzheimer’s disease, such as mild cognitive impairment, have been shown to have reduced gamma oscillations, Mody said.
Other studies attempted to employ neuromodulation techniques to stimulate gamma oscillations to restore memory. Auditory, visual, or transcranial magnetic stimulation at a frequency of 40 Hz (similar to the frequency of a cat’s purr) worked to dissolve plaques in the brain, but again showed no noticeable cognitive improvements, Mody said. In this latest study, Mody and his team sought to approach the problem from a different perspective. If they couldn’t kick-start these memory circuits using external tools, perhaps there was a way to trigger these electrical rhythms from within using a molecule.
Specifically, they needed a compound that targeted certain fast-firing neurons, known as paravalbumin interneurons, which are critical for generating gamma oscillations and, therefore, memory and cognitive functions. However, certain chemical receptors on these neurons that respond to the chemical messenger known as GABA act like brake pedals to slow down the gamma oscillations driven by these neurons.
Alzheimer’s model mice that received the treatment were able to remember the escape hole in the maze at a rate similar to that of wild-type mice without the disease.
Mody, John, and their team identified the compound DDL-920 to antagonize these receptors, allowing neurons to sustain more powerful gamma oscillations. To test whether this would actually result in improved memory and cognition, the researchers used mice that were genetically modified to have symptoms of Alzheimer’s disease.
Both these Alzheimer’s model mice and wild-type mice underwent baseline cognitive testing in a Barnes maze, a circular platform surrounded by visual cues and containing an escape hole. The maze is used to measure the rodents’ ability to learn and remember the location of the escape hole.
Following initial testing, the researchers orally administered DDL-920 to Alzheimer’s model mice twice a day for two weeks. After treatment, these animals were able to remember the escape hole in the maze at a rate similar to wild-type mice. In addition, the treated mice did not show any abnormal behavior, hyperactivity, or other visible side effects over the two-week period.
Mody said that while the treatment was effective in mice, much more work will be needed to determine whether it would be safe and effective in humans. If it ultimately proves effective, the drug could prove useful in treating other diseases and health problems in which decreased gamma oscillations occur, such as depression, schizophrenia and autism spectrum disorder, Mody said. “We’re very excited about it because of the novelty and the mechanism of action that hasn’t been addressed in the past,” he said.
