A new potential target for Alzheimer’s disease has been identified by researchers at the University of Leeds and Lancaster University. Their study in mice demonstrated that reducing the activity of the enzyme PDE4B may protect against Alzheimer’s disease (AD) pathology and be a useful treatment approach.

The findings were published in Neuropsychopharmacology in an article titled, “Protective effect of PDE4B subtype-specific inhibition in an App knock-in mouse model for Alzheimer’s disease.”

“Meta-analysis of genome-wide association study data has implicated PDE4B in the pathogenesis of Alzheimer’s disease (AD), the leading cause of senile dementia,” the researchers wrote. “PDE4B encodes one of four subtypes of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4A–D). To interrogate the involvement of PDE4B in the manifestation of AD-related phenotypes, the effects of a hypomorphic mutation (Pde4bY358C) that decreases PDE4B’s cAMP hydrolytic activity were evaluated in the AppNL-G-F knock-in mouse model of AD using the Barnes maze test of spatial memory, 14C-2-deoxyglucose autoradiography, thioflavin-S staining of β-amyloid (Aβ) plaques, and inflammatory marker assay and transcriptomic analysis (RNA sequencing) of cerebral cortical tissue.”

PDE4B is an enzyme inside cells that breaks down a molecule known as cyclic AMP, which regulates a range of cellular processes. Based on an Australian study that identified the PDE4B gene as a risk factor for developing AD, the researchers investigated whether reducing PDE4B activity might protect against AD pathology. They introduced a gene for reduced PDE4B activity into an AD mouse model that develops amyloid plaques in the brain.

The researchers observed that AD mice showed memory deficits in maze tests, but memory was unimpaired in AD mice with genetically reduced PDE4B activity. Using functional brain imaging, the team found the metabolism of glucose, the main source of energy in the brain, was impaired in AD mice, like that 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 then looked at gene and protein expression levels in the brain. They observed increased inflammation in the brains of AD mice, like that seen in Alzheimer’s disease patients, but inflammation was lower in AD mice with genetically reduced PDE4B activity.

Their data suggest that reducing PDE4B activity might be a useful approach for the treatment of Alzheimer’s disease, although more research is needed to validate the use of drugs that target the enzyme.

“Reducing the activity of the PDE4B enzyme had a profound protective effect on memory and glucose metabolism in the AD mouse model, despite these mice showing no decrease in the number of amyloid plaques in the brain,” said Steven Clapcote, PhD, the lead researcher from the University of Leeds. “This raises the prospect that reducing PDE4B activity may protect against cognitive impairment not only in Alzheimer’s disease but also in other forms of dementia, such as Huntington’s disease.”

“These results offer real hope for the development of new treatments that will benefit patients with Alzheimer’s disease in the future,” explained Neil Dawson, a co-author of the paper, from Lancaster University. “It was intriguing to find that reducing PDE4B activity by just 27% could dramatically rescue memory, brain function, and inflammation in the AD mice. The next stage is to test whether PDE4B inhibiting drugs have similar beneficial effects in the AD mouse model, to test their potential efficacy in Alzheimer’s disease.”

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