November 1, 2003

The Institute for Aging and Alzheimerâ??s Disease Research and the Department of Pharmacology and Neuroscience will receive $8.6 million over a five-year period from the National Institute on Aging to study several mechanisms that influence brain aging.

â??We are nationally recognized for quality science,â? said James Simpkins, PhD, director of the Institute for Aging and Alzheimerâ??s Disease Research and chair of pharmacology and neuroscience. â??This confirms the excellence of our scientists and their research.

â??The grant will investigate the causes and consequences of normal brain aging,â? Dr. Simpkins said. â??We hope that by better understanding how the brain ages normally, we can pinpoint what happens when there are problems and develop therapies to address conditions like Alzheimerâ??s disease.

â??To receive a program project grant from the National Institutes of Health, of which the NIA is a part, individual research projects must be part of a program that is connected both theoretically and practically,â? Dr. Simpkins said. â??Each of these projects will be better because they are part of this interdependent group,â? he said. â??The discoveries made on each project will influence how the other investigations develop.â?

The research team includes Michael Forster, PhD, professor; Peter Koulen, PhD, assistant professor; Glenn Dillon, PhD, associate professor; Meharvan Singh, PhD, assistant professor; James Simpkins, PhD, professor and chair; Christopher de Fiebre, PhD, assistant professor, all of pharmacology and neuroscience, and Karan Singh, PhD, chair and professor of biostatistics. The project began Aug. 1.

Dr. Forster is interested in how brain oxidation relates to cognitive decline, coordination and motor skills, both in normal brain aging and in cases of Alzheimerâ??s and Parkinsonâ??s disease. In all of the bodyâ??s cells, the cellular machinery that makes energy produces reactive oxygen molecules called free radicals as a byproduct, he said. The free radicals are unstable and tend to react with other molecules, which is often dangerous to the machinery of other cells, Dr. Forster explained. Because cells are constantly generating energy and therefore producing some level of free radicals, the cells are constantly under attack, or exposed to oxidative stress, since they are always trying to fight off the damaging free radical molecules.

During the aging process, the battle is progressively lost, so the cells keep getting more and more damaged, Dr. Forster said. Brain cells do not typically replicate, so they cannot replace themselves, and over time, their function is disrupted. Once the cells begin to become damaged, they produce more free radicals, creating more damage and becoming trapped in this vicious cycle. Dr. Forster is investigating whether oxidative stress is a cause of Alzheimerâ??s disease and other milder age-related changes in the brain. â??If we understand how oxidative stress causes normal brain aging, we would have a lot of insight into how it is involved in Alzheimerâ??s disease,â? he said.

Dr. Koulen is studying a specific set of proteins inside nerve cells that are critical to the cellsâ?? functions and influence the properties of nerve cells affected with Alzheimerâ??s disease and age-related cognitive impairment. These proteins are responsible for controlling the release of calcium from stores inside a cell into the cell, which is important because small changes in calcium concentration and the shape and size of these changes are used by nerve cells to mediate important processes in the brain. Dr. Koulen said his teamâ??s goal is to determine where, how and when such changes occur in established model systems for Alzheimerâ??s disease and age-related cognitive impairment.

Drs. Meharvan Singh and Dillon are working together to study how progesterone relates to brain aging and understand how it communicates with the inside of the cell. Dr. Dillon is concentrating on channels called GABAA receptors that let chloride into the cell. When the GABAA receptor is activated, it causes the inhibition, or slowing down, of that cellâ??s activity. They theorize that long-term inhibition may underlie the nerve dysfunction that takes place in age-related diseases, Dr. Singh said. They believe that progesterone may help alleviate the slowing down of the nerve cells by inhibiting the GABAA receptor so that it stops letting chloride into the cells.

In addition, Dr. Singh is studying the involvement of specific sequences of biochemical events called signal transduction pathways and the regulation of certain proteins called neurotrophins that may help protect the nerve cell from age-related brain dysfunction. He said they hope that by better understanding the biology of aging, they may be able to develop treatments for the prevention of age-associated cognitive decline and neurodegenerative diseases.

Dr. Simpkins is studying the normal role of estrogens in brain structure and function during aging. His research addresses the impact of estrogen loss at menopause on cognitive decline, nerve cell loss and the changes in the brain that occur in Alzheimerâ??s disease. This research is built on a foundation of evidence that estrogens serve to protect the brain from many age-related conditions. Further, in collaboration with Dr. Meharvan Singh, he will determine the effects of combined therapy with estrogens and progesterones on age-related changes in brain function.

Dr. de Fiebre will analyze learning ability, or cognition, and psychomotor skills using laboratory models. He is interested in how these brain functions decline with aging in some individuals, but not in others. Dr. de Fiebre said he hopes to find out why some individuals demonstrate brain aging while others do not. â??By identifying the biochemical basis of brain aging, drugs or other treatments might be able to be developed to slow or reverse this debilitating and costly problem,â? he said.

Dr. Karan Singh and other biostatisticians from the School of Public Health will provide centralized statistical services and collaborative research support to the program projects and monitor the quality of experimental designs and statistical analyses. They will provide statistical expertise for the design, data management and analysis for the research projects.

â??We will be responsible for taking the enormous amounts of data the program project grant will generate and analyzing it to determine how the research findings are most significantly related to brain aging,â? he said.


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