Effects of specific inhibition of PDE4B on senescence-associated cognitive decline

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Cognitive ageing is a lifelong process of gradual, ongoing, yet highly variable changes in cognitive function that occurs as people get older. In the healthy aged brain, changes lead to cognitive decline that affects the performance of activities of daily living, such as driving a car, in the elderly and increase vulnerability to the development of neurodegenerative conditions like Alzheimer's disease. Treatment with a drug called rolipram, which reduces the activity of a family of four enzymes - PDE4A, PDE4B, PDE4C and PDE4D - has been shown to induce a variety of beneficial effects in aged (>18-month-old) mice, including improvements in learning and memory. Unfortunately, when rolipram was tested in humans, it caused severe nausea and vomiting, likely caused by inhibition of PDE4D. To develop a treatment for age-related cognitive decline that has the potential benefits of rolipram but without its unacceptable side-effects, we specifically inhibited PDE4B in young adult (12-week-old) mice by altering their PDE4B gene. We recently reported that these PDE4B-inhibited mice have enhanced learning and memory, more and stronger connections between nerve cells in the brain, and more generation of new nerve cells in a part of the brain called the hippocampus that is important for learning and memory. This project will find out whether the altered PDE4B gene has similar beneficial effects in age (18-month-old). Humans also have the PDE4B enzyme, so inhibiting it could have similar effects in elderly people affected by cognitive decline. Since it is not possible to alter the PDE4B gene in human patients, we also assess the cognitive effects of a selective PDE4B-inhibiting drug called A-33 in the aged mice. A-33 has previously shown cognitive benefits in a rat model of traumatic brain injury, so we think it may have similar effects in aged mice. Our results will help us decide whether PDE4B inhibition is worth pursuing as a new treatment for age-related cognitive decline.