Inhaled anesthetic modulation of amyloid beta(1-40) assembly and growth.
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 beta 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 beta(1-40), and reduce solubility of amyloid beta(1-40) monomer. Size-exclusion chromatography, analytical ultracentrifugation and photo-induced cross-linking experiments indicate halothane enhancement of oligomeric species having molecular weight approximately 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 beta(1-40) concentration necessary to initiate oligomer formation, probably by preferential binding to intermediate oligomers en route to fibril formation.
Carnini
Anna
A
Steacie Institute of Molecular Sciences, National Research Council, 100 Sussex Drive, Ottawa, Ontario, ON, Canada K1A 0R6. Anna.Carnini@nrc-cnrc.gc.ca
Lear
J D
JD
Eckenhoff
R G
RG
D016229:Amyloid beta-Peptides / Q000187:drug effects*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D002850:Chromatography, Gel / Q000379:methods; D006221:Halothane / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D010446:Peptide Fragments / Q000187:drug effects*; D013050:Spectrometry, Fluorescence / Q000379:methods; D013997:Time Factors; D014461:Ultracentrifugation
D016229:Amyloid beta-Peptides; D018685:Anesthetics, Inhalation; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D007530:Isoflurane; D006221:Halothane