New Promising Therapeutic Approach for Cognitive Disorders, Alzheimer’s Disease

Patrícia Silva, PhD avatar

by Patrícia Silva, PhD |

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mouse study of Alzheimer's

A study recently published in the journal Neuropsychopharmacology revealed that the inhibition of a gene called phosphodiesterase-4B (PDE4B) in mice enhances the animals’ cognitive abilities. The work was conducted by an international team of researchers and is entitled “Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition”.

Cognitive dysfunction is a central feature in dementia and psychiatric disorders. Enzymatic proteins called phosphodiesterases (PDE) are known to be involved in the learning, memory and higher cognitive functions of the brain. PDE4B in particular is important in the formation of the hippocampus, a brain region linked to memory and spatial navigation, considered a risk gene for psychiatric disorders.

In order to better understand the role of PDE4B, researchers generated genetically engineered mice with a defective, not functional form of the gene.

Researchers found that mice with depleted PDE4B activity had enhanced cognitive abilities in several learning and memory tests. The animals tended to learn faster, recall events for a longer period of time and were able to successfully solve complex exercises in comparison to normal mice. On the other hand, these unusually intelligent mice were less likely to feel anxiety or recall fear. In an experiment with cat urine, PDE4B-inhibited mice exhibited a decreased fear response in comparison to regular mice, suggesting that PDE4B inhibition might increase the animal’s risk-taking behavior.

The research team concluded that PDE4B inhibition might represent a promising therapeutic approach for disorders linked to anxiety, pathological fear memory such as post-traumatic stress disorder, and cognitive decline including Alzheimer’s disease.

“Cognitive impairments are currently poorly treated, so I’m excited that our work using mice has identified phosphodiesterase-4B as a promising target for potential new treatments.” said the study’s co-author Dr. Steve Clapcote from the University of Leeds’ School of Biomedical Sciences in a news release.

“In the future, medicines targeting PDE4B may potentially improve the lives of individuals with neurocognitive disorders and life-impairing anxiety, and they may have a time-limited role after traumatic events.” added the study’s lead author Dr. Alexander McGirr from the University of British Columbia.

The findings were reported in mice and have not been tested in humans yet, although humans also have the PDE4B gene. Researchers are developing drugs to inhibit PDE4B in animal models, to establish which ones can be evaluated in human clinical trials in the future.

Alzheimer’s disease is a neurodegenerative disorder characterized by cognitive and behavioral problems due to the loss of neurons responsible for memory and learning. It is the most common form of dementia in the elderly and can lead to severe loss of mental function. There is currently no cure for the disease and it is estimated that Alzheimer’s and dementia are responsible for more than 500,000 deaths in the United States and more than 44 million worldwide every year. By age 85, one in every three individuals will have Alzheimer’s disease.

“This study highlights a potentially important role for the PDE4B gene in learning and memory in mice, but further studies will be needed to know whether the findings could have implications for Alzheimer’s disease or other dementias. We’d need to see how this gene could influence memory and thinking in people to get a better idea of whether it could hold potential as a target to treat Alzheimer’s.” concluded Dr. Laura Phipps from the Alzheimer’s Research UK, who was not involved in the study. “There is currently a lack of effective treatments for dementia and understanding the effect of genes can be a key early step on the road to developing new drugs. With so many people affected by dementia, it is important that there is research into a wide array of treatment approaches to have the best chance of helping people sooner.”