Methylation of the imidazole side chains of the Alzheimer disease amyloid-beta peptide results in abolition of superoxide dismutase-like structures and inhibition of neurotoxicity.
The toxicity of the amyloid-beta peptide (Abeta) is thought to be responsible for the neurodegeneration associated with Alzheimer disease. Generation of hydrogen peroxide has been implicated as a key step in the toxic pathway. Abeta coordinates the redox active metal ion Cu2+ to catalytically generate H2O2. Structural studies on the interaction of Abeta with Cu have suggested that the coordination sphere about the Cu2+ resembles the active site of superoxide dismutase 1. To investigate the potential role for such structures in the toxicity of Abeta, two novel Abeta40 peptides, Abeta40(HistauMe) and Abeta40(HispiMe), have been prepared, in which the histidine residues 6, 13, and 14 have been substituted with modified histidines where either the pi- or tau-nitrogen of the imidazole side chain is methylated to prevent the formation of bridging histidine moieties. These modifications did not inhibit the ability of these peptides to form fibrils. However, the modified peptides were four times more effective at generating H2O2 than the native sequence. Despite the ability to generate more H2O2, these peptides were not neurotoxic. Whereas the modifications to the peptide altered the metal binding properties, they also inhibited the interaction between the peptides and cell surface membranes. This is consistent with the notion that Abeta-membrane interactions are important for neurotoxicity and that inhibiting these interactions has therapeutic potential.
Tickler
Anna K
AK
Howard Florey Institute of Medical Research, Victoria 3010, Australia.
Smith
Danielle G
DG
Ciccotosto
Giuseppe D
GD
Tew
Deborah J
DJ
Curtain
Cyril C
CC
Carrington
Darryl
D
Masters
Colin L
CL
Bush
Ashley I
AI
Cherny
Robert A
RA
Cappai
Roberto
R
Wade
John D
JD
Barnham
Kevin J
KJ
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D001665:Binding Sites; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D016166:Free Radical Scavengers / Q000737:chemistry; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D009498:Neurotoxins / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D013482:Superoxide Dismutase / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D016166:Free Radical Scavengers; D007093:Imidazoles; D009498:Neurotoxins; D010446:Peptide Fragments; D006639:Histidine; D003300:Copper; D013482:Superoxide Dismutase