Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease beta-amyloid.
Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles and amyloid plaques, which are abnormal protein deposits. The major constituent of the plaques is the neurotoxic beta-amyloid peptide (Abeta); the genetics of familial AD support a direct role for this peptide in AD. Abeta neurotoxicity is linked to hydrogen peroxide formation. Abeta coordinates the redox active transition metals, copper and iron, to catalytically generate reactive oxygen species. The chemical mechanism underlying this process is not well defined. With the use of density functional theory calculations to delineate the chemical mechanisms that drive the catalytic production of H2O2 by Abeta/Cu, tyrosine10 (Y10) was identified as a pivotal residue for this reaction to proceed. The relative stability of tyrosyl radicals facilitates the electron transfers that are required to drive the reaction. Confirming the theoretical results, mutation of the tyrosine residue to alanine inhibited H2O2 production, Cu-induced radicalization, dityrosine cross-linking, and neurotoxicity.
Barnham
Kevin J
KJ
Department of Pathology, University of Melbourne, Victoria, Australia. kbarnham@unimelb.edu.au
Haeffner
Fredrik
F
Ciccotosto
Giuseppe D
GD
Curtain
Cyril C
CC
Tew
Deborah
D
Mavros
Christine
C
Beyreuther
Konrad
K
Carrington
Darryl
D
Masters
Colin L
CL
Cherny
Robert A
RA
Cappai
Roberto
R
Bush
Ashley I
AI
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D003300:Copper / Q000378:metabolism / Q000494:pharmacology; D004579:Electron Transport; D006861:Hydrogen Peroxide / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D012995:Solubility; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D014443:Tyrosine; D003300:Copper; D006861:Hydrogen Peroxide; C007543:dityrosine; D000409:Alanine