A new evidence for DNA nicking property of amyloid beta-peptide (1-42): relevance to Alzheimer's disease.
Alzheimer's disease (AD) is a complex neurodegenerative disorder with a progressive mental deterioration manifested by memory loss. No definite etiology has been established for AD to date. Amyloid beta (Abeta) protein plays a central role in the pathology of AD through multiple pathways like oxidative stress, apoptosis etc. Recently, our laboratory first time has evidenced localization of Abeta immunoreactivity in apoptotic nuclei of degenerating AD brain hippocampal neurons and also showed that Abeta (1-42) binds and alters the helicity of DNA. The present study provided fundamental data on DNA nicking induced by Abeta. The results showed that Abeta (1-42) has DNA nicking activity similar to nucleases. Further, magnesium ion (1mM) enhanced DNA nicking activity of Abeta. The data on Abeta solution stability on DNA nicking revealed that the oligomers of Abeta (1-42) peptides showed more DNA nicking activity compared to monomers and fibrillar forms. The nuclease specific inhibitor aurintricarboxylic acid prevented the DNA nicking property of Abeta. Transmission electron microscopy (TEM) studies revealed that Abeta causes open circular and linear forms in supercoiled DNA and also clearly evidenced the physical association of protein-DNA complex. The above data indicated that Abeta mimics endonuclease behavior. Our finding of DNA nicking activity of Abeta peptides has biological significance in terms of causing direct DNA damage.
Suram
A
A
Department of Biochemistry and Nutrition, Central Food Technological Research Institute, Mysore 570020, India.
Hegde
M L
ML
Rao
K S J
KS
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D004278:DNA, Superhelical / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D004706:Endodeoxyribonucleases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008670:Metals / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D004278:DNA, Superhelical; D008670:Metals; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D001312:Aurintricarboxylic Acid; D004706:Endodeoxyribonucleases