Researchers have discovered that limiting a certain enzyme can have a dramatic impact in protecting against the effects of Alzheimer's disease. The finding could lead to a new class of drugs that fight the disease.
Much of the historical research into Alzheimer's disease has focused on plaques that form in the brain thanks to the accumulation of too much amyloid proteins. Recently, though, scientists have begun looking beyond the role of these proteins (which one study suggests may form in the liver) into other probable causes of the disease and its advancement. That's largely because amyloid-based plaques, while certainly a hallmark of the disease, don't seem to be a direct cause of it, as evidenced by the failure of drugs that try to target them.
In seeking another way forward, researchers at the University of Leeds (UL) and Lancaster University (LU) in the UK, turned to an Australian study that showed that having the gene for the production of an enzyme known as PDE4B was identified as a risk factor for developing Alzheimer's.
The enzyme is found in cells and is responsible for breaking down a molecule known as cyclic AMP, which is linked to many metabolic roles including the regulation of immune function and neurotransmitter synthesis. Interestingly, a 2015 study showed that limiting PDE4B expression gave mice a brainpower boost.
Once again looking at how suppressing PDE4B might affect the brain, the UK team genetically modified mice with Alzheimer's and amyloid plaques in the brain to have reduced PDE4B activity. The researchers found startling results on a number of fronts.
First, the mice with Alzheimer's and normal PDE4B expression showed memory loss when navigating a maze. But those who had the genetic modification to have less PDE4B activity showed no impairment at all. Second, the modified mice showed a normal level of glucose metabolism in their brains even though they had Alzheimer's disease (AD) and that function is usually diminished. Finally, the team observed that mice with less PDE4B activity had less inflammation in their brains than those with more of the enzyme – another hallmark of AD.
Real hope
Because all of these effects were found in mice that already had Alzheimer's – and the accompanying amyloid plaques – but had significant improvement in symptoms, the researchers say that further investigation into how to limit PDE4B in human patients with the condition could lead to new treatment pathways.
"These results offer real hope for the development of new treatments that will benefit patients with Alzheimer's disease in the future," said LU's Neil Dawson, a co-author of the study. "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."
Study co-author Steven Clapcote from LU, says he believes the findings might also help treat dementia beyond Alzheimer's.
"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," he said. "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." Huntington's is also marked by a build-up of plaques in the brain.
The study has been published in the journal Neuropsychopharmacology.
Source: Lancaster University