2015 ADDF Harrington Scholars
Carol A. Colton, Ph.D.
The Colton lab has taken an innovative approach by analyzing immune changes at different stages of Alzheimer’s disease-like diseases using a model that re-capitulates critical features of the immune response in humans.
Carol A. Colton, PhD is a Professor in the Department of Neurology at Duke University Medical Center.
The results of Dr. Colton’s recent studies clearly show that rather than immune-mediated “killing” through release of highly toxic factors, neurons die slowly by immune-mediated starvation. Our data show that microglia, the brain’s principal immune cell, exhibit an overactive enzyme-based metabolic pathway that deprives neurons of essential nutrients. Spearheaded by the enzyme known as arginase, this pathway normally uses arginine to help repair the brain.
In Alzheimer’s disease, instead of repair, the hyperactive arginase pathway reduces arginine within the brain. Neurons are very sensitive to loss of arginine and slowly starve to death. We can interrupt this arginine deprivation by using DFMO, a drug that blocks the arginase pathway. When we treat younger mice at the beginnings of disease before severe pathology occurs, we block Alzheimer’s disease-like damage to the brain.
Importantly, data from human brain now show that the same mechanism is likely to take place in humans with Alzheimer’s disease. These on-going studies provide a unique insight into how an “out of control” immune response can be brought back under control to slow or reduce the progression of Alzheimer’s disease.
Dr. Colton completed her PhD at Rutgers University. After two assistant professorships and work as a Special Expert with the NIH, she served as a Professor of Physiology at Georgetown University Medical School for over a decade. Dr. Colton joined the faculty at Duke University in 2000, where she additionally serves as Program Director for the 3rd Year Medical Student Neuroscience Program. She is a member of the American Physiological Society, the Society for Neuroscience, the American Society for Neurochemistry and the International Society of Neurochemistry.
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Jerri M. Rook, Ph.D.
Dr. Rook and her team of scientists in the Vanderbilt Center for Neuroscience Drug Discovery are focused on discovery of novel therapeutic strategies for the treatment of Alzheimer’s disease and other cognitive disorders.
Dr. Rook is an Assistant Professor of Pharmacology at Vanderbilt University in the Vanderbilt Center for Neuroscience Drug Discovery.
Alzheimer’s disease is the most common form of dementia and is characterized by the progressive decline in cognitive function. Current treatments provide little to no improvement in symptomology or disease progression. A significant number of preclinical behavioral and human clinical studies provide strong evidence that enhanced cholinergic transmission via activation of muscarinic acetylcholine receptor subtype 1 (M1) may have exciting therapeutic potential for the treatment of cognitive impairments of Alzheimer’s disease.
The Vanderbilt Center for Neuroscience Drug Discovery has developed a highly potent, selective series of M1 positive allosteric modulators (PAMs) with enhanced physiochemical and pharmacokinetic properties for in vivo studies, providing an unprecedented opportunity to evaluate the potential of selective potentiation of M1 as a novel treatment of symptoms associated with Alzheimer’s disease. As opposed to direct activation of M1, PAMs dramatically potentiate the response of the receptor to its endogenous ligand acetylcholine, offering high selectivity while maintaining normal spatiotemporal signaling patterns.
Behavioral studies with these compounds demonstrate robust efficacy in multiple preclinical rodent models of improved cognitive performance. Furthermore, preliminary safety studies demonstrate no adverse effects in rodents, dogs, or nonhuman primates. Current studies are focused on assessing the safety profile of our lead compound, VU001-M1, prior to first in human studies. If successful, these studies would pave the way for development of a novel class of drugs to treat the cognitive deficits associated with Alzheimer’s disease and other cognitive disorders.
Dr. Rook received her Ph.D. degree in Pharmacology from the University of Kansas Medical Center. She then pursued her postdoctoral studies at Vanderbilt University. She is currently a member of the American Society for Pharmacology and Experimental Therapeutics, Society for Neuroscience, and International Society for Neurochemistry. Dr. Rook has received multiple awards including the Ruth L. Kirschstein National Research Service Award from the National Institute of Mental Health in 2009, the Alzheimer's Drug Discovery Foundation and Charles River Laboratories International, Inc. 2011 partnership award, and is the recent recipient of the Edward N. & Della L. Thome Memorial Foundation award program in Alzheimer's disease drug discovery research.
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