A healthy brain is powered by trillions of synapses—the dynamic connections where neurons exchange information with one another as we experience the world around us. This process, known as synaptic plasticity, serves as the foundation for learning and memory.
For some time, researchers have known that neurodegenerative disorders like dementia and Alzheimer’s disease disrupt synaptic plasticity by causing the formation of plaques and tangles in the brain. But little has been understood about exactly how this happens, and even less on how to treat it.
Now, results from a new report, published recently in Nature Neuroscience, are showing that a group of investigators has discovered a key mechanism—involving the proteins PTEN and beta-amyloid—in Alzheimer’s disease-related memory loss.
"The PTEN gene normally functions to limit cell growth. So, when you inhibit PTEN gene function cells it increases growth, which can have negative consequences such as causing cancer and autism," explains Bryan Luikart, PhD, an assistant professor of physiology and neurobiology at the Geisel School of Medicine, whose own research has shed light on the role of PTEN mutations in autism disorders. "However, in this study they have shown that the growth promoting effects of PTEN inhibition can be harnessed to improve neuron function in a neurodegenerative disease."
Mark Spaller, PhD, an associate professor of pharmacology and toxicology at Geisel, and adjunct associate professor of chemistry at Dartmouth College, whose lab played a key role in the study, talks about these groundbreaking findings and their implications for better understanding and treating Alzheimer’s disease.
Q: Can you tell us about the overall research effort and what it was focused on?
Spaller: The research, led by Jose Esteban at the University of Madrid in Spain, represents many years of work by a multi-institutional group of labs spanning several countries. The team that was assembled for this project was quite large and diverse, involving all manner of skill sets—including chemistry, biochemistry, cell biology, and animal biology.
The Esteban lab had been investigating PTEN for a few years, and wanted to understand the role it might play in disrupting synaptic connections. Jose and I had successfully collaborated on a different project earlier in our careers, and knowing my lab’s interest in developing molecular therapeutics, he contacted me to see if we could assist in this newer project. Jose and his colleagues did a fantastic job in identifying, in a mouse model, this new key mechanism, where one of the pathological agents of Alzheimer’s disease basically floods the synapses with the PTEN protein and impairs memory.
Q: What role does PTEN usually play in the body?
Spaller: When not mutated, PTEN is a protein with important and desirable properties as a tumor suppressor, and it’s also involved in aiding synaptic plasticity. Since cognitive functions require a very fine balance of the right proteins, having PTEN present in normal amounts is a good thing. But when there is unregulated, excessive importing of PTEN in the cell, it causes this problem with neuronal activity and can impair memory formation.
Q: How did your lab contribute to the study?
Spaller: Our contribution involved the design and preparation of the compounds that were used in both the cell-based and mouse studies. My lab specializes in the discovery of molecules called peptides that can be tailor-made to interfere with targets—certain proteins within a cell that are misbehaving, if you will, and contributing to a disease state—and inhibit their association.
To use a metaphor, if you think of the many different interacting proteins inside of a cell as occupying a crowded dance floor, what we try to do is find a way to “cut in” on one specific couple out of the many hundreds that are present. In this particular case, we developed a compound that interfered with the interaction of PTEN, so that it would not be recruited as rapidly into cells. As a result, our colleagues were able to successfully reduce memory loss in mice.
Q: How is your lab following up on this work?
Spaller: We’re attempting to develop next-generation compounds that will prove more effective. We’re hoping that these may serve as valuable molecular research tools to further investigate the underlying biology, and serve as lead compounds for developing drugs to treat memory loss associated with Alzheimer’s disease via a fundamentally new mechanism.
It’s going to take considerable additional work, of course, to reach the stage where it would be appropriate for use in humans. For now, at least we’ve proven that it’s possible to externally introduce a molecule and see an internal correction to this problem—which is the essence of molecular therapeutics.