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2007 Grant - M. Lee
Beta-Amyloid and Monoaminergic Neurodegeneration in Alzheimer's Disease Transgenic Mice
Michael K. Lee, Ph.D.
Johns Hopkins University
2007 Investigator-Initiated Research Grant
Two characteristics of Alzheimer's disease are degeneration of neurons in the cerebral cortex of the brain and the appearance in the same brain region of dense protein aggregates called amyloid plaques. The neurons that degenerate are predominantly "cholinergic" neurons, meaning that they communicate with each other by using a small chemical messenger called acetylcholine. The plaques are made up mostly of a small toxic peptide called beta-amyloid. Determining the relationship between cholinergic neurodegeneration and beta-amyloid is crucial for understanding the disease, but progress has been hampered by the lack of good animal models — most mice engineered to overproduce beta-amyloid show no signs of neurodegeneration.
Michael Lee, Ph.D., and colleagues have developed a genetically engineered mouse that overproduces beta-amyloid and shows substantial neurodegener-ation in a different subset of neurons called "monoaminergic" neurons. These specialized neurons, found in the brain stem rather than the cortex, use chemical transmitters called monoamines to communicate with other neurons. In this animal model, the axons, or long processes that neurons extend out to other neurons, begin to die first, followed by the cell body itself. The same type of neurons are, in fact, damaged in some human cases of Alzheimer's disease. Because these monoaminergic neurons are intimately involved in processing emotions, this damage may be related to severe depression and aggression seen in late stages of the disease.
The model suggests that beta-amyloid toxicity alone can cause neurodegener-ation in the mouse brain and provides an opportunity to study that process and to evaluate neuroprotective strategies. The researchers will use this model to study beta-amyloid-induced neurodegeneration in depth. They also plan to look more closely at other neuronal populations, especially cholinergic neurons, to see if they also degenerate in this mouse model.