As Alzheimer’s disease becomes an unwelcome visitor in more and more homes, patients and their families cling to the hope that someday there will be more effective treatments.
Now a team of scientists in Belgium reports that tests involving mice show promise for reducing amyloid plaques in the brain and improving memory in Alzheimer’s patients.
Amantha Thathiah, Ph.D., and her colleagues focused on blocking a receptor called GPR3 (G-protein coupled receptor 3). The receptor is a protein that in humans is controlled by the GPR3 gene.
The tests were done at Catholic University at Leuven in association with the Flanders Institute for Biotechnology.
Thathiah said an initial study screened genes to identify their potential, and GPR3 emerged.
“We try not to have too many expectations [of what we’ll find],” she told Healthline. “We wanted to know how, actually, is it affecting changes in amyloid pathology.”
Targeting the Proteins
More than half of Alzheimer’s drugs currently on the market target this type of receptor, the Flemish team noted.
Their research suggests that GPR3 may offer a highly “druggable” target for Alzheimer’s disease. Abnormal clusters of protein fragments known as amyloid-β damage the brains of those with Alzheimer’s disease. It is the most common cause of dementia.
It has been difficult for drug developers to translate animal studies in the lab to clinical trials of Alzheimer’s disease patients.
Thathiah said they introduced mutations with a human transgene into the test mice. The researchers used four different genetic mouse models of Alzheimer’s disease to probe the effects of deleting GPR3. They found that deleting GPR3 reduced plaque formation and deposits across all four models.
Using a technique for visualizing whole brains in 3-D, the researchers found that plaque had cleared in the mouse brains that were without GPR3. When they administered a battery of behavioral tests, one mouse model showed improved learning, memory, and social skills.
Moving Toward Trials
Thathiah said their initial discoveries were first published in 2009.
“For the last five years, we’ve been validating, publishing, trying to understand the mechanism,” she said. “We want to get it into drug trials. It’s a real viable target for the disease.”
News of possible advances in dealing with the scourge of Alzheimer’s usually attract cautious optimism from other scientists.
Such is the case with Marcie Glicksman, Ph.D., a neuroscientist who has spent more than 20 years working on developing therapeutics for neurodegenerative diseases and is currently vice president of biology at Orig3n in Boston.
Orig3n is a biotechnology company devoted to the understanding and treatment of rare genetic diseases.
“Any new compelling target for Alzheimer’s disease has my vote to move forward as a possible therapeutic strategy,” Glicksman told Healthline. “The fact that they have a compound that shows activity in multiple animal models is a positive, but since we don’t have any indication that one or more of the animal models for Alzheimer’s disease is predictive for impacting the disease, it is still unclear how to weigh this evidence.”
She said it was critically important to use the animals to help predict possible toxicities as well as to understand how the compound is affecting the target.
“The important next steps are to understand about the biology of the target in vivo in order to understand how it may be helpful to counter the functional deficits in Alzheimer’s disease,” said Glicksman. “It is also important to work out a target-related biomarker that can be used when a drug first goes into humans to establish that your drug is modulating the target in humans and determine the best dose.”
Because GPR3 is involved in signal transduction pathways, it has the potential for many pleiotropic effects (that is, the production by a single gene of two or more apparently unrelated effects).
To make that point, Glicksman cited an October 2015 study in Scientific Reports indicating that mice lacking GPR3 become obese as they age. So it is important to understand what types of unintended consequences any new compound could have.