Alzheimer's Disease (AD) is a common, progressive, dementing disorder that is devastating to the patient and family. Memory loss is often its earliest and most prominent symptom. The memory loss may be due, in part, to the hippocampal cell less observed in AD. The cause of cell death is unclear, but an important clue may come from the observation that amyloid is deposited in the disorder. While the reasons for amyloid deposition and its effects on neurons are still debated, many studies support the hypothesis that amyloid is toxic to neurons. The mechanism by which amyloid may exert a toxic effect is unknown. Several lines of evidence, however, suggest that it may affect neuronal calcium homeostasis. In addition, several other factors may affect intracellular calcium in aged, adult hippocampal neurons including altered calcium binding proteins, increased calcium influx through NMDA receptors, and the normal activation of memory processes in hippocampus that require large calcium influxes. In combination with these three factors, amyloid may raise intracellular calcium levels across the threshold for calcium- mediated, excitotoxic cell death. The mechanism by which amyloid might raise intracellular calcium is unknown.
Specific Aims 1 and 2 are to test the hypotheses that amyloid increases calcium influx through voltage-dependent calcium channels and/or NMDA receptors. Currents will be measured using the blind, whole-cell, patch-clamp recording technique in the hippocampal slice preparation. Calcium influx will be compared between neurons in which the recording electrode contains vehicle or scrambled beta1-42 and ones which contain beta1-42. An adult preparation will be used and the slices will be obtained acutely in order to replicate some of the conditions present in AD. Understanding the mechanism of amyloid toxicity might help in designing treatments that prevent progression of Alzheimer;s disease. It may also help explain why memory and the hippocampus are so prominently involved in AD. It is anticipated what the results of this pilot project will be the basis for a subsequent full-length proposal further examining the mechanisms of amyloid-mediated cell death and how the three other factors noted above may contribute to that cell death.
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