West LA Times

In a new study, a molecule identified and synthesized by UCLA Health researchers was shown to restore cognitive functions in mice with symptoms of Alzheimer’s disease by effectively jumpstarting the brain's memory circuitry.

If proven to have similar effects in humans, the candidate compound would be novel among Alzheimer’s disease treatments in its ability to revitalize memory and cognition, study authors said.

“There is really nothing like this on the market or experimentally that has been shown to do this,” said study lead author Dr. Istvan Mody, the Tony Coelho Professor of Neurology and distinguished professor of physiology at UCLA Health.

The molecule, DDL-920, works differently from recent FDA-approved drugs for Alzheimer’s disease such as lecanemab and aducanumab, which remove harmful plaque that accumulates in the brains of Alzheimer’s disease patients. While removing this plaque has been shown to slow the rate of cognitive decline, it does not restore memory or remedy cognitive impairments.

“They leave behind a brain that is maybe plaqueless, but all the pathological alterations in the circuits and the mechanisms in the neurons are not corrected,” Mody said.

In the study, published in The Proceedings of the National Academy of Sciences journal, UCLA researchers led by Dr. Istvan Mody and Dr. Varghese John, a professor of neurology and director of the Drug Discovery Laboratory (DDL) at the Mary S. Easton Center for Alzheimer's Disease Research and Care at UCLA sought to find a compound that could figuratively flip the switch back on in the brain’s memory circuitry.

Similar to a traffic signal, the brain fires off electric signals at different rhythms 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 Alzheimer’s disease symptoms 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 hertz – similar to the frequency of a cat’s purr – worked to dissolve plaques in the brain but again did not show notable cognitive enhancements, Mody said.

In this latest study, Mody and his team sought to tackle the problem from a different perspective. If they could not jump-start these memory circuits using external tools, perhaps there was a way to trigger these electrical rhythms from inside using a molecule.

Specifically, they needed a compound to target certain fast-firing neurons known as parvalbumin interneurons that are critical in generating gamma oscillations and therefore memory and cognitive functions. However, certain chemical receptors in these neurons that respond to Gamma-aminobutyric acid (GABA) work like brake pedals reducing gamma oscillations entrained by these neurons.

Mody, John and their team identified DDL-920 as an antagonist for these receptors allowing neurons to sustain more powerful gamma oscillations.

To test whether this would result in improved memory and cognition researchers used mice genetically modified with symptoms of Alzheimer’s disease.

Both these Alzheimer’s disease-model mice and wild-type mice underwent baseline cognitive testing in a Barnes maze – a circular platform surrounded by visual clues containing one escape hole. The maze measures how well rodents can learn and remember escape hole locations.

After initial tests researchers orally administered DDL-920 twice daily for two weeks. Following treatment Alzheimer's model mice recalled escape holes similarly as wild-type mice without displaying abnormal behavior hyperactivity or other visible side effects over two weeks period

Mody stated while effective much more work is needed determining safety effectiveness humans Should ultimately prove effective drug implications treatments other diseases health conditions diminished gamma oscillations depression schizophrenia autism spectrum disorder

“We are very enthusiastic about that because of novelty mechanism action tackled past” Mody said