Alzheimer's disease (AD) is the most common type of dementia in the elderly. Amyloid-b-.peptides (Ab) accumulation in senile plaques is characteristically found in brains from AD patients. In vivo and in vitro evidence suggests that Ab is toxic to neurons. The goal of our research is to understand the mechanisms underlying brain dysfunction and neuronal degeneration in AD. To investigate Ab effects on neuronal populations we have developed diverse in vitro models. Because the basal forebrain is severely affected in AD, and because we are experienced in the physiology and anatomy of this brain structure, basal forebrain models were selected for our research. Initially, we used hybrid septal-neuroblastoma (SN) cell lines to demonstrate that SN56 cells are vulnerable to Ab but SN48 cells are resistant to the peptide. In contrast to SN48 cells, SN56 cells express prominent outward potassium (K+) currents (IK) that are enhanced by Ab. This 'K enhancement precedes the detection of cell death and attenuation of 'K protects these cells from Ab-induced toxicity. These observations led us to hypothesize that the enhancement of specific K+ conductances may lead to neuronal dysfunction and subsequent cell death. Because the tumoral properties of cell lines may influence results, more recently we have developed preparations containing basal forebrain neurons and collected data from these neurons. Our new data suggest that AB enhances 'K in basal forebrain cholinergic neurons. This proposal focuses on the investigation of basal forebrain K+ channels, the mechanisms underlying Ab-induced K+ channel alteration, and the consequences of Ab-altered K+ channels on neuronal function and viability. Data from this work may contribute to the development of specific therapies designed to decrease neuronal dysfunction and vulnerability in AD. Furthermore, this work will contribute to our understanding of basal forebrain physiology.
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