Cognitive decline occurs after anesthesia and surgery, and is most pronounced in the elderly and perhaps in those with pre-existing neurodegenerative disorders. Loss of cognition appears to be unrelated to type of surgery, suggesting that anesthesia may contribute. Our research into inhaled anesthetic-protein interactions shows that these small hydrophobic ligands can potently promote protein oligomerization especially in small, unstable peptides. Our molecular hypothesis for this is that inhaled anesthetics shift oligomerization equilibria through preferential binding to numerous intermolecular cavities in the oligomer. Since such oligomerization is thought to be a proximal pathogenic event in the neurodegenerative disorders like Alzheimer's, Parkinson's and Huntington's diseases, inhaled anesthetics would be predicted to accelerate these disorders. We propose to test this hypothesis with in vitro molecular, and cell culture systems.
Specific aim 1 will establish the feasibility of this hypothesis by examining the effect of seven general anesthetics on oligomerization of different amyloid beta peptides using light scattering, electron microscopy, binding assays, size exclusion chromatography and ultracentrifugation. A primary goal of aim 1 is to establish a rank-order of oligomerization potency.
Specific aim 2 will test whether these in vitro observations translate into enhanced cytotoxicity or apoptosis of amyloid beta in cell culture, using the rank order to establish a link to the aim 1 mechanism. These studies will provide the feasibility to extend this hypothesis to animal models and ultimately to clinical studies of the interaction between anesthetics and neurodegeneration.
|Carnini, Anna; Lear, J D; Eckenhoff, R G (2007) Inhaled anesthetic modulation of amyloid beta(1-40) assembly and growth. Curr Alzheimer Res 4:233-41|
|Carnini, Anna; Eckenhoff, Maryellen Fazen; Eckenhoff, Roderic G (2006) Interactions of volatile anesthetics with neurodegenerative-disease-associated proteins. Anesthesiol Clin 24:381-405|