Novel drug-like molecule developed to halt memory loss

A new class of experimental drug-like small molecules is showing great promise in targeting a brain enzyme to prevent early memory loss in Alzheimer’s disease, scientists claim.

Developed in the laboratory of D. Martin Watterson, from Northwestern University, the molecules halted memory loss and fixed damaged communication among brain cells in a mouse model of Alzheimer’s.

“This is the starting point for the development of a new class of drugs. It’s possible someday this class of drugs could be given early on to people to arrest certain aspects of Alzheimer’s,” said Watterson, lead author of the study.

Changes in the brain start to occur 10 to 15 years before serious memory problems become apparent in Alzheimer’s.

“This class of drugs could be beneficial when the nerve cells are just beginning to become impaired,” said Linda Van Eldik, a senior author of the paper and director of the University of Kentucky Sanders-Brown Center on Aging.

The novel drug-like molecule, called MW108, reduces the activity of an enzyme that is over-activated during Alzheimer’s and is considered a contributor to brain inflammation and impaired neuron function.

Strong communication between neurons in the brain is an essential process for memory formation.

“I’m not aware of any other drug that has this effect on the central nervous system,” Watterson said.

Watterson and his collaborators have a new National Institutes of Health (NIH) award to further refine the compound so it is metabolically stable and safe for use in humans and develop it to the point of starting a phase 1 clinical trial.

The compound strikes at a new, single target that has long flown under the radar in Alzheimer’s drug development. The target is a stress-related protein kinase, p38alpha MAPK.

In a key memory experiment in the study, mice brains were injected with beta-amyloid, whose increase is one hallmark of Alzheimer’s in humans. One group of mice was then administered MW108 and another group was administered a placebo.

Next, each group of mice was taught environmental cues to learn how to swim through a water maze to find a resting platform.

Then the mice were placed in a different arm of the maze and tested on their ability to remember the location of the platform based on the environmental cues.

The mice administered MW108 found the resting platform in the water maze as quickly as a control group of mice. The mice given the placebo made more mistakes and took longer to find the platform. They also had difficulty learning the location of the resting platform during the teaching phase.

“The results show the compound prevented the cognitive impairment,” Van Eldik said.

The study will be published in the journal PLOS ONE.

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