Title: Effects of specific inhibition of PDE4B on age-related cognitive decline
Funder: Dunhill Medical Trust

Abstract: The overall aim of the proposed research is to increase knowledge of the effects of specific inhibition of PDE4B on age-related cognitive decline in laboratory mice. PDE4B is one of four enzymes (PDE4A-D) that selectively hydrolyse cAMP. Rolipram, which inhibits all PDE4 subtypes, has shown a variety of therapeutic effects in aged mice (Clapcote et al., 2017). However, the drug causes nausea and emesis in humans, owing to PDE4D-specific effects, thus limiting its use for therapeutic purposes. To develop a treatment for cognitive decline in the elderly that has the potential benefits of rolipram, but without the nausea, we have focussed on specific inhibition of PDE4B. To this end, we generated mice that have a catalytic mutant form of PDE4B with a 27% decreased ability to hydrolyse cAMP. We recently reported that these mice show enhanced learning and memory; enhanced long-term potentiation and less synaptic depression in hippocampal slices; increased dendritic spine density in the hippocampus and amygdala; and enhanced neurogenesis in the adult dentate gyrus (McGirr et al., 2016). In this project, we will quantify the effects of the mutant PDE4B on cognition, synaptic plasticity and neuroinflammation in aged C57BL/6 mice. Our research will investigate the cognitive effects of inhibition of PDE4B by complementary pharmacological (PDE4B-selective compounds) and genetic (PDE4B mutation) approaches in APP knock-in mice. To interrogate the translational potential of PDE4B inhibition as a therapeutic intervention for elderly people with cognitive impairment, we will also investigate in aged C57BL/6 mice the cognitive effects of a compound (A-33) that selectively inhibits PDE4B over PDE4D, and has been reported to enhance learning after traumatic brain injury in rats (Titus et al., 2016). This duel approach will help us to distinguish between cognitive effects resulting from PDE4B inhibition beginning in utero (genetic) versus in old age (pharmacological). Our results will be critical in deciding whether specific inhibition of PDE4B is a strategy worth pursuing as a therapeutic intervention for age-related cognitive decline.

Lay abstract: 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. In this project, we will find out whether the altered PDE4B gene has similar beneficial effects in aged (18-month-old) mice. Human beings 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 been reported to enhance learning after traumatic brain injury in rats, so we think it could have similar pro-cognitive 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.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL