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A potential turning point in Alzheimer’s treatment has come out of UCLA Health, where scientists have identified a compound that can restore memory function in mice with symptoms of the disease. This groundbreaking discovery, which centers around a molecule called DDL-920, could pave the way for a novel approach to treating Alzheimer’s that goes beyond simply slowing the progression of the disease. The study, published in The Proceedings of the National Academy of Sciencesshowed that DDL-920 effectively “boosted” the brain’s memory circuits.
Alzheimer’s disease is a progressive neurological disorder that primarily affects older adults and leads to a deterioration in memory, cognitive abilities, and eventually the ability to perform simple daily tasks. The disease is characterized by the accumulation of amyloid plaques and tau fibrils in the brain, which disrupt communication between neurons and ultimately lead to cell death.
Over time, this neuronal loss leads to significant shrinkage of the brain and a decline in cognitive functions, including memory, thinking skills, and the ability to perform everyday tasks. Alzheimer’s disease is the most common cause of dementia and has no cure, making it one of the most pressing public health challenges in the face of the world’s aging population.
Existing therapies, including some recently approved drugs, focus on reducing the amyloid plaques in the brain that are a hallmark of the disease. While these treatments can slow the progression of cognitive decline, they cannot reverse the damage that has already occurred in the brain, particularly the loss of memory and cognitive function.
Recognizing the limitations of existing treatments, the UCLA team set out to develop a new strategy. Instead of focusing on removing amyloid plaques, they wanted to find a way 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, high-frequency brain rhythms that are important for memory and cognition. In people with Alzheimer’s disease, these oscillations are significantly reduced, leading to impaired cognitive function.
The research team identified a molecule called DDL-920 that could potentially target and increase the activity of these parvalbumin interneurons. DDL-920 was designed to block certain receptors in these neurons that normally act as brakes and slow down gamma oscillations. By inhibiting these receptors, the researchers hoped to increase the activity of the neurons and restore normal oscillation patterns, thereby revitalizing the memory circuits.
To test the effectiveness of DDL-920, researchers conducted experiments on genetically modified mice that showed symptoms of Alzheimer’s disease. Both these mice and healthy mice were subjected to a cognitive task known as the Barnes maze. This task involves a circular platform with an escape hole and is used to measure spatial learning and memory in rodents.
After assessing the mice’s baseline cognitive abilities, the researchers gave the Alzheimer’s model mice DDL-920 twice daily for two weeks. They then tested the mice again to see if their ability to remember and find the escape hole had improved.
After the two-week treatment period, the Alzheimer’s model mice treated with DDL-920 performed almost as well as the healthy mice on the Barnes maze, indicating a significant improvement in memory. These treated mice were able to remember the location of the escape hole almost as well as their healthy counterparts, a promising sign that the compound had successfully restored some level of cognitive function.
The researchers observed no behavioral abnormalities in the treated mice, nor side effects such as hyperactivity or other motor disorders that often complicate the development of new neurological drugs. The lack of visible side effects was particularly encouraging and suggests that DDL-920 could be a safe candidate for further testing in humans.
While these results are promising, researchers caution that much work is needed before DDL-920 can be considered a viable treatment for humans. The next steps include rigorous testing to ensure the compound is safe and effective for humans. This includes researching the appropriate dosage, understanding how the compound is metabolized in the human body, and determining potential long-term side effects.
The study opens up new possibilities for treating other neurological disorders characterized by reduced gamma oscillations, such as depression, schizophrenia and autism spectrum disorders. DDL-920’s ability to enhance these oscillations suggests it may have broader applications beyond Alzheimer’s disease, potentially benefiting individuals with a range of cognitive impairments.
Authors of the study “A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice” are 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.
