Researchers from Yale’s Strittmatter Laboratory have discovered a molecular compound that reverses memory deficits in genetically modified mice, opening new pathways for the development of pharmaceutical therapies targeting Alzheimer’s disease.
Injecting mouse embryos with a gene known to cause Alzheimer’s in humans produces a strain of mice that exhibit symptoms mimicking the early stages of the disease. In particular, damage to synapses — links between neurons that allow them to exchange information — leads to reduced performance on memory tasks in affected mice.
Using this animal model, a research team led by Stephen Strittmatter, School of Medicine professor of neurology and director of the Alzheimer’s Disease Research Center, and Erik Gunther, School of Medicine research scientist in neurology, identified a set of polymers that can cross the blood-brain barrier and restore cognitive function when administered orally. The results of their work were published on Jan. 2 in the journal Cell Reports.
“The biggest implication of the findings is that there could someday be a drug or medicine that people can take orally that can impact the outcome for Alzheimer’s disease. Ideally it would be something that could be taken in an early stage before symptoms even develop,” said Janie Merkel, the director of the Yale Center for Molecular Discovery.
Gunther said that the pharmaceutical intervention used in the study targets a specific point in the Alzheimer’s disease process that previous work has largely ignored. The onset of Alzheimer’s disease is thought to be driven by the build-up of a protein fragment called beta-amyloid, which is produced throughout the cortex of the brain in aging adults and eventually aggregates into hard, permanent clusters called plaques.
When the molecular precursors to amyloid plaques bind to a certain class of receptor sites, called PrPs, this triggers a cascade that physically degrades the synapses responsible for communication between cells. Neural damage in this vein translates to cognitive deficits such as memory loss, difficulty speaking and impaired executive control.
“Most of the therapeutic approach to Alzheimer’s [historically] has been centered around either reducing the production of [beta-amyloid], or clearing it when it’s there,” Gunther said. “The vast majority of clinical trials have taken that approach, and they’ve been largely unsuccessful.”
Strittmatter’s research team chose a different strategy, focusing on cutting off harmful interactions between neurons and the molecules that form plaques, so that the plaques may coexist benignly alongside healthy brain tissue.
To this end, the team screened several thousand molecules that seemed likely to inhibit such interactions by blocking PrPs, said Austin Stoner ’20, who works as a research assistant in Strittmatter’s lab. In particular, the team found that one polymeric compound was particularly effective for reversing pathology in genetically modified mouse populations.
Merkel noted that one of the biggest challenges of Alzheimer’s is that people who show symptoms are so far down the disease pathway that it is difficult to reverse. So, if the pharmaceutical treatment tested in this study is developed into a drug for human use, it will most likely be prescribed as a preventative therapy for individuals with a high risk of developing Alzheimer’s disease.
Merkel said that there are several potential routes for further research once funding has been secured, including studying additional models of mouse disease and moving to other organisms.
Every 66 seconds, someone in the United States develops Alzheimer’s, according to the Alzheimer’s Association.
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