A new evidence for DNA nicking property of amyloid β-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 (Aβ) 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 Aβ immunoreactivity in apoptotic nuclei of degenerating AD brain hippocampal neurons and also showed that Aβ (1-42) binds and alters the helicity of DNA. The present study provided fundamental data on DNA nicking induced by Aβ. The results showed that Aβ (1-42) has DNA nicking activity similar to nucleases. Further, magnesium ion (1 mM) enhanced DNA nicking activity of Aβ. The data on Aβ solution stability on DNA nicking revealed that the oligomers of Aβ (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 Aβ. Transmission electron microscopy (TEM) studies revealed that Aβ 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 Aβ mimics endonuclease behavior. Our finding of DNA nicking activity of Aβ peptides has biological significance in terms of causing direct DNA damage.