In a new study, a molecule identified and synthesized by researchers at UCLA Health was shown to restore cognitive functions in mice with symptoms of Alzheimer’s disease by effectively triggering the brain’s memory circuits.
If proven to have similar effects in humans, the candidate compound would be new among Alzheimer’s disease treatments in its ability to revitalize memory and cognition, the study authors said.
There’s really nothing comparable on the market or experimentally shown to do this.”
Dr. Istvan Mody, lead author and professor of neurology and physiology, UCLA Health
The molecule, DDL-920, works differently than recent FDA-approved drugs for Alzheimer’s disease, such as lecanemab and aducanumab, which remove harmful plaque that builds up in the brains of Alzheimer’s patients. Although removing this plaque has been shown to slow cognitive decline, it does not restore memory and cognitive impairment.
“They leave behind a brain that may be plaque-free, but all the pathological changes in the circuits and the mechanisms in the neurons are not corrected,” Mody said.
In the study, published in the journal The Proceedings of the National Academy of SciencesUCLA researchers led by Dr. Istvan Mody and 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, sought to find a compound that figuratively Turn the switch back on in the brain’s memory circuit.
Like a traffic light, the brain fires electrical signals at different rhythms to start and stop different functions. Gamma oscillations are among the highest frequency rhythms and have been shown to orchestrate the brain circuits underlying cognitive processes and working memory – the type of memory used to remember a telephone 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 use 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 notable cognitive improvements, Mody said.
In this latest study, Mody and his team tried to tackle the problem from a different perspective. If they couldn’t trigger these memory circuits using external tools, perhaps there was a way to activate these electrical rhythms from within using a molecule.
Specifically, they needed a compound to target certain fast-firing neurons, known as the paravalbumin interneurons, which are crucial in generating gamma oscillations and thus memory and cognitive functions. However, certain chemical receptors in these neurons that respond to the chemical messenger known as GABA act like brake pedals to reduce the gamma oscillations carried by these neurons.
Mody, John and their team identified the compound DDL-920 to antagonize these receptors, allowing the neurons to support more powerful gamma oscillations.
To test whether this would actually result in improved memory and cognition, researchers used mice genetically modified to have symptoms of Alzheimer’s disease.
Both these Alzheimer’s disease model mice and the wild-type mice underwent a basic cognitive test in a Barnes maze – a circular platform surrounded by visual cues and with one escape hole. The maze is used to measure how well rodents can learn and remember the location of the escape hole.
After initial testing, researchers administered DDL-920 orally to the Alzheimer’s model mice twice daily for two weeks. After treatment, the mice with Alzheimer’s disease were able to remember the escape hole in the maze at the same rate as the wild-type mice. Furthermore, the treated mice showed no abnormal behavior, hyperactivity or other visible side effects during the two-week period.
Mody said that while the treatment was effective in mice, much more work would be needed to determine whether the treatment would be safe and effective in humans. Should it ultimately prove effective, the drug could have implications for treatments of other diseases and health conditions that have reduced gamma oscillations, such as depression, schizophrenia and autism spectrum disorders, Mody said.
“We’re very excited about that because of the novelty and the mechanism of action that hasn’t been addressed in the past,” Mody said.
Source:
Magazine reference:
Wei, X., et al. (2024). A therapeutic small molecule enhances γ oscillations and improves cognition/memory in Alzheimer’s disease model mice. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2400420121