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

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.

The overall aim of the proposed research is to increase knowledge of the effects of specific inhibition of PDE4B on senescence-associated 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. 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. We will quantify the effects of the mutant PDE4B on cognition, synaptic plasticity and neuroinflammation in aged C57BL/6 mice. To interrogate the translational potential of PDE4B inhibition as a therapeutic intervention for elderly people with cognitive impairment, and in the current absence of
compounds that specifically target PDE4B, we will also investigate the cognitive effects of compounds that selectively inhibit PDE4B over PDE4D in aged C57BL/6 mice. 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.

Senescence-associated cognitive decline 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, functional and morphological changes lead to cognitive and sensorimotor control decline that affect the performance of activities of daily living (ADL), such as driving a car, in the elderly and increase vulnerability to the development of neurodegenerative conditions. People in the UK are living longer, on average, than ever before. The number of people aged 75 and over has grown by 47% since mid-1974. By 2032, the over 65s are projected to make up 25% of the UK's population. Considering this increase in the proportion of elderly humans, it is important to identify a means for maintaining cognitive integrity by protecting against, or even counteracting, the ageing process.

With increases in life expectancy, an increasing proportion of life may be lived with cognitive impairment as age increases. Maintaining optimal cognitive function with age is thus an important of part healthy ageing across the lifespan. We believe that our studies will ultimately lead to the development of improved, novel means by which age-associated cognitive decline can be treated. This belief is based on the strength of our recent published data showing cognitive enhancement in young adult PDE4B-inhibited mice, as well as recent publications reporting pro-cognitive effects of a PDE4B-selective compound in a rat model of traumatic brain injury affected by neuroinflammation. Therefore, the ultimate impact of this research will be with elderly individuals affected by cognitive decline. Such benefit is long-term and will require exploitation of the new information which will be gained as a direct result of this project.

A more immediate impact will affect researchers interested in the fundamental biology of phosphodiesterases and cAMP signalling, and will have considerable significance for researchers into the physiological and biochemical basis of cognitive ageing. The regulation of the cAMP signalling pathway by PDE4 represents an attractive target for therapeutic intervention, so our findings on PDE4B will also offer clues to academics and commercial interests seeking new routes to therapy. This will include academic and industrial researchers, those involved with drug design, as well as research-active clinicians.

In the mid- to long-term, we anticipate that any therapeutically useful approaches arising (e.g. based on specific inhibition of PDE4B) will benefit pharmaceutical companies through informing programmes of rational drug design aimed at treatment of cognitive ageing and CNS diseases in which cognition is impaired. Indeed, major pharmacological companies have already supplied us with PDE4B-selective compounds for this project.

Additional impact will be delivered through the provision of skilled people to the workforce. The postdoctoral fellow will receive training in cutting edge methods and approaches (electrophysiology, imaging, transgenic models, behavioural approaches etc.); he/she will be able to apply these skills in their future career. Additionally, a number of undergraduate students (~10 per year) will be able to participate in cutting-edge research during their final-year research projects in our laboratories.