The radical model of Alzheimer's disease: specific recognition of Gly29 and Gly33 by Met35 in a beta-sheet model of Abeta: an ONIOM study.
The Radical Model of Alzheimer's Disease (AD) is presented in some detail. The model provides a unified picture for the role of the amyloid beta peptide (Abeta), Met35, copper ions, oxygen, beta sheet secondary structure, and the generation of hydrogen peroxide, in mediating oxidative stress in AD. It predicts a role for glycyl radicals as long-lived species which can transport the damage into cell membranes and initiate lipid peroxidation. Previous work has established the thermodynamic and kinetic viability of most of the steps. In the present work, QM/MM and Amber calculations reveal that self assembly of antiparallel beta-sheet which brings Met35 into the required close proximity to a glycine residue is more likely if the residue is Gly29 or Gly33, than any of the other four glycine residues of Abeta.
Brunelle
Patrick
P
Department of Chemistry, University of Calgary, Calgary, AB, Canada, T2N 1N4.
Rauk
Arvi
A
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008715:Methionine / Q000502:physiology*; D008956:Models, Chemical; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010455:Peptides / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D010455:Peptides; D017382:Reactive Oxygen Species; D008715:Methionine; D006861:Hydrogen Peroxide; D005998:Glycine