Novel phage peptides attenuate beta amyloid-42 catalysed hydrogen peroxide production and associated neurotoxicity.
Amyloid-beta (Abeta) peptides play a central role in the pathogenesis of Alzheimer's disease. There is accumulating evidence that supports the notion that the toxicity associated with human Abeta (both 40 and 42) is dependent on its superoxide dismutase (SOD)-like activity. We developed a novel screening method involving phage display technology to identify novel peptides capable of inhibiting Abeta's neurotoxicity. Two random peptide libraries containing 6-mer and 15-mer peptide inserts were used and resulted in the identification of 25 peptides that bound human Abeta (40 or 42). Here, we show that two of the three most enriched peptides obtained significantly reduced Abeta42's SOD-like activity. A 15-mer peptide reduced Abeta42 neurotoxicity in a dose-dependent manner as evidenced by a reduction in LDH release. These findings were confirmed in the independent MTT assay. Furthermore, comparative analysis of the 15-mer peptide with Clioquinol, a known inhibitor of Abeta's metal-mediated redox activity, showed the 15-mer peptide to be equipotent to this metal chelator, under the same experimental conditions. These agents represent novel peptides that selectively target and neutralise Abeta-induced neurotoxicity and thus provide promising leads for rational drug development.
Taddei
K
K
Centre of Excellence for Alzheimer's Disease Research and Care, School of Exercise, Biomedical & Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
Laws
S M
SM
Verdile
G
G
Munns
S
S
D'Costa
K
K
Harvey
A R
AR
Martins
I J
IJ
Hill
F
F
Levy
E
E
Shaw
J E
JE
Martins
R N
RN
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001435:Bacteriophages / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D007464:Clioquinol / Q000494:pharmacology; D004926:Escherichia coli / Q000821:virology; D005821:Genetic Techniques; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017422:Sequence Analysis, DNA; D013482:Superoxide Dismutase / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D019151:Peptide Library; D010455:Peptides; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D007464:Clioquinol; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D006836:Hydro-Lyases; C045581:lactate dehydratase