Abstract

Anesthesia and surgery have been reported to produce long-term cognitive problems, and to accelerate neurodegenerative disorders in the elderly. In previous work, we found that inhaled anesthetics enhance fibril formation and cytotoxicity of amyloid β peptide. In this work we show that the inhaled anesthetics halothane (2-bromo-2-chloro-1,1,1- trifluoroethane) and isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) also favor intermediate oligomers of amyloid β1-40, and reduce solubility of amyloid β1-40 monomer. Size-exclusion chromatography, analytical ultracentrifugation and photo-induced cross-linking experiments indicate halothane enhancement of oligomeric species having molecular weight ∼44-100 kDa. Bis-ANS fluorescence experiments revealed that halothane stabilizes a population of diffusible oligomers relative to the monomer or the mature fibril. These data show that inhaled anesthetics lower the amyloid β1-40 concentration necessary to initiate oligomer formation, probably by preferential binding to intermediate oligomers en route to fibril formation.

Keywords: Alzheimer's disease, intermediates, protein cavities, analytical ultracentrifugation, bis-ANS fluorescence, neurodegeneration, inhaled anesthetics