Numerous recent reports indicating that apoptotic mechanisms may be involved in excitotoxic cell death and that apoptotic mechanisms mediate neuronal degeneration in various CNS diseases, including Alzheimer's disease (AD), proposed the applicant to undertake a series of studies, the long term goal of which was to clarify the role of excitotoxic versus apoptotic neurodegeneration in AD. Comparing a prototype example of apoptosis (physiological cell death, PCD, which occurs naturally in the developing CNS) with several examples of excitotoxic neurodegeneration, we determined that by ultrastructural criteria, excitotoxic and apoptotic neurodegeneration are two totally separate and distinct phenomena. In the course of these studies, we discovered that by administering NMDA antagonist drugs, including PCP, ketamine or ethanol, to infant rodents we can trigger a massive wave of apoptotic neurodegeneration in several major regions of the developing brain. Thus, it appears that NMDA glutamate receptors are sensitive mediators of neuronal cell death in the developing brain. Either too much or too little glutamate stimulation can kill neurons; too much kills by an excitotoxic mechanism and too little by an apoptotic mechanism. These findings have potentially important public health implications, but in addition they provide the neurobiologist with a new model for mass producing apoptotic neurodegeneration in the in vivo mammalian brain and studying mechanisms that initiate and drive this cell death process as well as methods for preventing it. In project #2, we will study the morphological characteristics, biochemical pathways and genomic mechanisms of this apoptotic process, explore methods for preventing it and develop methods for distinguishing it from excitotoxic or other non-apoptotic cell death processes. Methods developed in project #2 will be applied both in project #1 and project #2 ti determine whether neuronal degeneration occurs by this apoptotic mechanism in certain adult rodent models for studying AD, or in the human AD brain.
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