New Compound Restores Memory in Alzheimer’s Mouse Model

A new molecule developed by University of California Los Angeles (UCLA) researchers can restore lost cognitive functions in mice with symptoms of Alzheimer's disease, according to a new study published in PNAS.

If effective in humans, the molecule has potential to be developed into a novel treatment to restore memory and cognition in Alzheimer’s patients.

Alzheimer’s drug development: a different approach

There have been some recent success stories in the development of drugs to treat Alzheimer’s disease. Some, such as lecanemab and donanemab, target and remove abnormal proteins that form harmful plaques in the brain thought to be involved in the progression of the disease. However, these drugs have shown only modest success in slowing patients’ rate of cognitive decline.

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“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,” said Dr. Istvan Mody, a professor of neurology and physiology at UCLA and the senior author of the study.

Mody and colleagues aimed to find a compound that could turn back the clock for impairments in the brain’s memory circuitry observed in Alzheimer’s. To do this, their new compound – known as DDL-920 – works in a different way to existing treatments.

“There is really nothing like this on the market or experimentally that has been shown to do this,” Mody said.

Targeting gamma oscillations

The researchers targeted their drug development toward a type of brain signal called gamma oscillations, which are known to be reduced in some patients with early Alzheimer’s disease. These oscillations are involved in brain circuits underlying cognition and working memory.

Previous studies conducted in mice have tried to stimulate gamma oscillations in the brain to restore memory using auditory or visual stimulation at a frequency of 40 Hz. While these did dissolve some of the harmful plaques in the brain in mouse models, they did not result in notable cognitive improvements.

Nevertheless, Mody and colleagues took a slightly different approach, using a chemical compound to stimulate memory circuits from the inside instead of external stimuli.

They developed DDL-920 to target receptors on the fast-firing neurons that help generate gamma oscillations. The compound works by antagonizing receptors for a molecule called GABA, which work as brake pedals for the gamma oscillations produced by these neurons. With DDL-920 blocking this brake mechanism, the neurons can sustain their gamma oscillations.

DDL-920 was then put to the test in mice genetically modified to have symptoms of Alzheimer’s. The mice underwent experiments to measuring their cognitive ability using a Barnes maze, which tested their ability to learn and remember the exit.

Mice with Alzheimer’s symptoms treated with DDL-920 twice daily over a two-week period were able to recall the maze’s escape hole at a similar rate to normal mice and did not display any abnormal behavior or side effects during their treatment.

More research required before human trials

Mody suggests that much more research is needed to determine if the treatment is safe and effective in humans, but that the drug could have implications for treatments of other conditions that have diminished gamma oscillations such as depression, schizophrenia and autism spectrum disorder.

“We are very enthusiastic about that because of the novelty and the mechanism of action that has not been tackled in the past,” Mody said.

Reference: Wei X, Campagna JJ, Jagodzinska B, et al. A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice. PNAS. 2024;121(33):e2400420121. doi: 10.1073/pnas.2400420121

This article is a rework of a press release issued by UCLA. Material has been edited for length and content.