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Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer's disease β‐amyloid
Author(s) -
Barnham Kevin J.,
Haeffner Fredrik,
Ciccotosto Giuseppe D.,
Curtain Cyril C.,
Tew Deborah,
Mavros Christine,
Beyreuther Konrad,
Carrington Darryl,
Masters Colin L.,
Cherny Robert A.,
Cappai Roberto,
Bush Ashley I.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1890fje
Subject(s) - chemistry , reactive oxygen species , neurotoxicity , tyrosine , amyloid (mycology) , electron transfer , biochemistry , amyloid beta , peptide , biophysics , photochemistry , toxicity , biology , organic chemistry , inorganic chemistry
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 β‐amyloid peptide (Aβ); the genetics of familial AD support a direct role for this peptide in AD. Aβ neurotoxicity is linked to hydrogen peroxide formation. Aβ 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 H 2 O 2 by Aβ/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 H 2 O 2 production, Cu‐induced radicalization, dityrosine cross‐linking, and neurotoxicity.