A Compensatory Approach to Reversing Brain Wave Disruption in Alzheimer's Disease
Researchers here provide animal model evidence for a novel approach to improve cognitive function in Alzheimer's disease. It is focused on neurons that maintain specific neural rhythms in the brain, necessary for the coordination of neural network activity that occurs during normal cognitive functions. These gamma waves appear to be important to memory functions, as well as many other aspects of brain health. They are observed to be disturbed in a number of neurological conditions. This approach is essentially compensatory, but the size of the effect is large, and therefore may be worth using even in an environment in which the brain is still being attacked by the underlying pathology of neurodegenerative conditions.
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 the memory and cognitive impairments. "They leave behind a brain that is maybe without plaque, but all the pathological alterations in the circuits and the mechanisms in the neurons are not corrected."
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.
Researchers thought that perhaps there was a way to trigger these electrical rhythms from inside cells using a molecule. Specifically, they needed a compound to target certain fast-firing neurons, known as the paravalbumin interneurons, that are critical in generating gamma oscillations and therefore memory and cognitive functions. However, certain chemical receptors in these neurons that respond to the chemical messenger known as GABA work like brake pedals to reduce the gamma oscillations entrained by these neurons. Researchers identified the compound DDL-920 to antagonize these receptors, allowing the neurons to sustain more powerful gamma oscillations.
Alzheimer's disease model mice and wild-type mice underwent baseline cognitive testing in a Barnes maze - a circular platform surrounded by visual clues and containing one escape hole. The maze is used to measure how well rodents can learn and remember the location of the escape hole. After the initial tests, researchers orally administered DDL-920 to the Alzheimer's model mice twice daily for two weeks. Following treatment, the Alzheimer's disease model mice were able to recall the escape hole in the maze at similar rates as the wild-type mice. Additionally, the treated mice did not display any abnormal behavior, hyperactivity, or other visible side effects over the two-week period.
Link: https://www.uclahealth.org/news/release/molecule-restores-cognition-memory-alzheimers-disease-model