Neuroscience
Discovery of TRPM2 Inhibitors for the Treatment of Neuroinflammation
2023 ADDF-Harrington Scholar
Much Alzheimer’s disease (AD) research focuses on protein misfolding in the brain, which is linked to the toxic accumulation of soluble amyloid-beta oligomers. However, the role of the immune system in the etiology of AD is often overlooked.
“In an attempt to better understand the inherent complexity of Alzheimer's disease, we are focusing on it more as an immune disorder and trying to understand how and why the immune system in the brain goes awry,” Dr. Weaver said.
According to Dr. Weaver, microglia, the resident immune cells of the brain, represent one of the key mediators of enhanced immune-mediated neuroinflammatory responses in AD. The normal spectrum of microglial responses is intended to promote bacteria/virus elimination, tissue repair and functional recovery. In neurodegenerative disorders, however, the microglia become excessively pro-inflammatory and release neurotoxic factors.
Dr. Weaver and his colleagues have found that by blocking Transient Receptor Potential Melastatin 2 (TRPM2), a receptor on the surface of microglia, they can dramatically lessen microglial proinflammatory activation with minimal effect on beneficial anti-inflammatory activation. They are seeking to develop a small molecule therapeutic agent which will be effective at reducing or shutting down the negative aspects of microglia.
“The beta amyloid approach to treating Alzheimer’s disease as primarily a neurologic disorder is not dead, but by no means is it the whole story,” Dr. Weaver said. “We need other approaches and other avenues, and the immune system and microglia are the front runners in these approaches.”