Study rules out potential treatment target for Alzheimer's

An unexpected result discovered by neuroscientists at Western University won’t prevent the formation and growth of Alzheimer’s disease but it potentially rules out a major potential treatment focus that drug manufacturers – and researchers around the world – have been targeting for years in the fight against the debilitating disease.

In a recent study from BrainsCAN, Western’s $66 million Canada First Research Excellence Fund program in cognitive neuroscience, Stefan Everling and his collaborators Susheel Vijayraghavan and Alex Major found that overstimulation of muscarinic M1 receptors actually disrupts and even blocks working memory activity, which contradicts long-held beliefs about the function of these receptors found in the brain.

The study, published by the high-impact journal Neuron, showed that proactive stimulation of acetylcholine – an organic chemical that functions in the brain and body of many types of animals, including humans, as a messenger for neural information – in human brain models did not garner the intended positive result of increasing memory but in fact, completely stunted the retention of newly acquired information.

“There have been a lot of studies from many laboratories that suggest that activating M1 receptors should enhance cognitive activity and we wanted to test that hypothesis,” says Vijayraghavan, a research scientist in the Everling Lab and lead writer of the paper. “When we activated these receptors we found the opposite. The activity in these cells was shut down because of these receptors, which is intriguing given the evidence to the contrary.”

M1 receptors are the most abundant kind of muscarinic receptors in the prefrontal cortex, a region of the brain crucially involved in cognition so they are a major target for drugs and other therapeutics for Alzheimer’s disease. Now scientists like Everling and his team can focus on M2 receptors, which are far less prevalent in the human brain but may be a more attractive target for developing cognitive enhancers.

“M1 receptors are like docking stations for chemicals in the brain,” says Everling, a Professor of Physiology and Pharmacology at Western’s Schulich School of Medicine & Dentistry and a scientist at Western’s Robarts Research Institute. “We thought activating these receptors would help but it actually hurts memory. This study essentially depreciates one class – an abundant class – of these docking stations as potential clinical targets.”

Worldwide, nearly 44 million people have Alzheimer’s or a related dementia. By 2050, costs associated with dementia could be as much as $1.1 trillion.