A potential breakthrough in the treatment of Alzheimer’s has been announced from UCLA Health. Scientists have identified a compound that can restore memory function in mice exhibiting symptoms of Alzheimer’s. The groundbreaking discovery centers around a molecule called DDL-920, and could pave the way for new approaches to treating Alzheimer’s that go beyond simply slowing the progression of the disease. The study, published in the Proceedings of the National Academy of Sciences, demonstrated that DDL-920 effectively “activated” memory circuits in the brain.
Alzheimer’s disease is a progressive neurological disorder that primarily affects older adults, resulting in a decline in memory, cognitive abilities, and ultimately the ability to perform simple daily tasks. The disease is characterized by the accumulation of amyloid plaques and tau protein deposits in the brain, which disrupt communication between neurons and ultimately lead to cell death.
Over time, this loss of neurons leads to significant brain atrophy and a decline in cognitive functions such as memory, reasoning, and the ability to perform familiar tasks. Alzheimer’s disease is the most common cause of dementia and, with no cure, represents one of the most pressing public health challenges as the world’s population ages.
Existing treatments, including recently approved drugs, focus on reducing the amyloid plaques in the brain that characterize the disease. Although these treatments can slow the progression of cognitive decline, they cannot reverse damage already done to the brain, particularly loss of memory and cognitive function.
Recognizing the limitations of existing treatments, the UCLA team set out to explore a new strategy: instead of focusing on removing amyloid plaques, they aimed to find ways to restore the brain’s memory circuits.
The researchers focused on a specific type of brain cell called parvalbumin interneurons. These cells are known to generate gamma oscillations, a high-frequency brain rhythm that is essential for memory and cognition. In people with Alzheimer’s, these oscillations are significantly reduced, leading to impaired cognitive function.
The research team identified a molecule, DDL-920, that could target and enhance the activity of these parvalbumin interneurons. DDL-920 was designed to block specific receptors within these neurons that normally act as brakes, slowing down gamma oscillations. By inhibiting these receptors, the researchers hoped to boost neuronal activity, restoring normal oscillatory patterns and activating memory circuits.
To test the efficacy of DDL-920, the researchers performed experiments on mice genetically engineered to show symptoms of Alzheimer’s disease. They subjected both these mice and healthy mice to a cognitive task called the Barnes maze, which features a circular platform with a single escape exit and is used to measure spatial learning and memory in rodents.
After assessing the mice’s baseline cognitive abilities, the researchers administered DDL-920 twice daily to Alzheimer’s disease model mice for two weeks, then retested the mice to see if they had improved their ability to remember and find their way out.
After a two-week treatment period, Alzheimer’s model mice given DDL-920 performed nearly as well as healthy mice in the Barnes maze, demonstrating significantly improved memory. These treated mice were also able to recall the location of the escape route nearly as well as healthy mice, a promising sign that the compound restored some cognitive function.
The researchers observed that treated mice did not exhibit any abnormal behaviors or side effects, such as hyperactivity or other motor dysfunction, that often complicate the development of new neurological drugs. The lack of visible side effects is particularly encouraging, suggesting that DDL-920 may be a safe candidate for further testing in humans.
While these findings are promising, the researchers caution that much more research is needed before DDL-920 can be considered an effective treatment for humans. The next step will be rigorous testing to ensure the compound is safe and effective for humans. This includes figuring out appropriate dosages, understanding how the compound is metabolized in the human body, and identifying potential long-term side effects.
“This study opens new avenues for the treatment of other neurological disorders characterized by reduced gamma oscillations, including depression, schizophrenia, and autism spectrum disorder. The ability of DDL-920 to enhance these oscillations suggests that it may have broad applications beyond Alzheimer’s disease, benefiting people with a range of cognitive disorders.”
The study, “Therapeutic small molecules enhance gamma oscillations and improve cognition/memory in Alzheimer’s disease model mice,” was authored by Xiaofei Wei, Jesus J. Campagna, Barbara Jagodzinska, Dongwook Wi, Whitaker Cohn, Jessica T. Lee, Chunni Zhu, Christine S. Huang, László Molnár, Carolyn R. Houser, Varghese John, and Istvan Mody.
