‘A clear mechanistic link’

LA JOLLA, Calif.—Given the impending healthcare burden as baby boomers age, Alzheimer's disease continues to be one of the biggest research targets lately, and that dedication is paying off with new discoveries. One of the latest developments comes from a collaboration among the Salk Institute, the Sanford-Burnham Medical Research Institute and others institutions, in which researchers have defined a key mechanism behind the progress of Alzheimer's disease.

In 2009, Stephen F. Heinemann, a professor in Salk's Molecular Neurobiology Laboratory, discovered that a nicotinic receptor known as Alpha7 may help to trigger Alzheimer's disease. Gustavo Dziewczapolski, a staff researcher in Heinemann's lab, noted that previous studies had pointed to a possible interaction between Alpha7 receptors and amyloid beta. In mice induced with Alzheimer's disease, some with the gene for Alpha7 receptors and some without, the team discovered that while both sets of mice developed the amyloid beta plaques the disease is infamous for, only those with the genes for Alpha7 receptors showed the cognitive impairments associated with the disease.

Building off of that work, this latest discovery has revealed a cellular signaling cascade in which amyloid beta stimulates the Alpha7 receptors, which in turn trigger astrocytes to release extra glutamate into synapses. Glutamate is a signaling chemical, an excitatory neurotransmitter that plays a significant role in our ability to learn and store memories. In normal conditions, glutamate is an essential part of normal function in neuronal synapses. But when astrocytes add additional glutamate to the mix, synapses are overrun with excitatory signals, which in turn activates a set of receptors outside of the synapse known as extrasynaptic-N-methyl-D-aspartate receptors (eNMDARs). These eNMDARs depress synaptic function, resulting in the memory loss and confusion Alzheimer's disease is known for.

Heinemann and Dziewczapolski detailed this discovery in a recent paper published in the Proceedings of the National Academy of Sciences, along with Juan Piña-Crespo, Sara Sanz-Blasco, Stuart A. Lipton of the Sanford-Burnham Medical Research Institute and their collaborators at Howard Hughes Medical Research Institute, the Technion-Israel Institute of Technology, Jinan University, Panorama Research Institute, the Scripps Research Institute and the UCSD School of Medicine.

According to Dziewczapolski, there are multiple avenues by which they can pursue this research. Alpha7 antagonists are capable of blocking amyloid beta from binding with the Alpha7 receptors, and he notes that the team is "currently contacting companies synthesizing Alpha7 compounds in order to obtain small drugs to test in our animal model." Partial agonists or full agonists of the receptor would also work, he adds. Alpha7 receptors "play an important role in cellular events such as neurotransmitter release, second messenger cascades, cell survival, apoptosis and inflammatory responses," Dziewczapolski explains. He notes that several pharmaceutical companies—including Roche, AstraZeneca, Abbott, EnVivo Pharmaceuticals, Targacept and Memory Pharmaceuticals—are developing agonists, partial agonists, antagonists and allosteric modulators against Alpha7 receptors, though "with the focus on its cognitive enhancement properties, but not under the framework of the mechanism underlying Alzheimer's disease revealed in our work."

Additionally, a drug already exists that can target the other aspect of this pathway: NitroMemantine, developed by the Lipton's Laboratory, might block the entry of eNMDARs into this cascade.

"Both Alpha7 receptors and eNMDARs represent, in my opinion, promising targets for drug development as disease-modifying therapeutics for Alzheimer's disease," says Dziewczapolski.

Dziewczapolski adds that the team has an opportunity to use their animal model to test some Alpha7 nAChR compounds under development by various companies, noting that "having access to some Alpha7 receptor ligands from these companies will help us further characterize the extension of this Alzheimer's disease underlying mechanism and its potential as a target for therapeutic intervention."

"Thanks to the joint effort of our colleagues and collaborators, we seem to finally have a clear mechanistic link between a key target of the amyloid beta in the brain, the Alpha7 nicotinic receptors, triggering downstream harmful effects associated with the initiation and progression of Alzheimer's disease," said Dziewczapolski. "This is a clear demonstration of the value of basic biomedical research. Drug development cannot proceed without knowing the details of interactions at the molecular and cellular level. Our research revealed two potential targets, Alpha7Rs and eNMDARs, for future disease-modifying therapeutics, which Dr. Heinemann and I both hope will translate in a better treatment for Alzheimer's patients."

Support for this work came from the U.S. National Institutes of Health, the U.S. Department of Defense, the National Institute of Neurological Disorders and Stroke, the American Heart Association and the Ministry of Education and Science of Spain.