Researchers from the University of Leeds and Lancaster University in the United Kingdom have identified a new potential target for the treatment of Alzheimer’s disease: PDE4B.
Alzheimer’s disease is the leading cause of dementia and disability in old age. As the number of people diagnosed with Alzheimer’s disease increases, new treatments are urgently needed to improve the quality of life of people living with the disease.
PDE4B is an enzyme within cells that breaks down a molecule known as cyclic AMP, which regulates a variety of cellular processes. Building on an Australian study that identified the PDE4B gene as a risk factor for developing Alzheimer’s disease, the UK team investigated whether reducing PDE4B activity could protect against Alzheimer’s disease pathology and be a useful treatment approach. To this end, they introduced a gene to reduce PDE4B activity in a mouse model of Alzheimer’s disease (AD) that develops amyloid plaques in the brain, a key pathological feature of the disease.
The researchers observed that AD mice showed memory deficits in maze tests, but memory was not affected in AD mice with genetically reduced PDE4B activity. Using functional brain imaging, the team found that glucose metabolism, the main source of energy in the brain, was altered in AD mice, as seen in patients with the disease. However, AD mice with genetically reduced PDE4B activity showed healthy levels of glucose metabolism in the brain.
To understand the mechanisms involved, the researchers next looked at gene and protein expression levels in the brain. This identified increased inflammation in the brains of AD mice, like that seen in patients with Alzheimer’s disease, but inflammation was lower in AD mice with genetically reduced PDE4B activity. Similar effects were observed for other proteins involved in Alzheimer’s disease pathology. Overall, these data suggest that reducing PDE4B activity could be a useful approach for the treatment of Alzheimer’s disease, although more research is needed to validate the use of drugs targeting the enzyme.
Dr Steven Clapcote, lead researcher at the University of Leeds, said: “Reducing the activity of the PDE4B enzyme had a profound protective effect on memory and glucose metabolism in the AD mouse model, despite that these mice did not show any decrease in the number of amyloid plaques in the brain, raising the possibility that reducing PDE4B activity may protect against cognitive decline not only in Alzheimer’s disease but also in other forms. of dementia, such as Huntington’s disease.
Dr Neil Dawson, co-author of the paper, from Lancaster University, echoed these sentiments: “These results offer real hope for the development of new treatments that will benefit patients with Alzheimer’s disease in the future. It was Intriguing to discover that reducing PDE4B activity by just 27% could dramatically rescue memory, brain function and inflammation in AD mice. “The next stage is to test whether PDE4B inhibitor drugs have similar beneficial effects in the mouse model of AD, to test their potential efficacy in Alzheimer’s disease.”
The research was published in the journal Nature Portfolio. Neuropsychopharmacology and was supported by Dunhill Medical Trust, BBSRC, Alzheimer’s Research UK and the Scientific and Technological Research Council of Turkey.