First evidence for helical transitions in supercoiled DNA by amyloid Beta Peptide (1-42) and aluminum: a new insight in understanding Alzheimer's disease.

Overview

Previously, we evidenced a B --> Z helical change in Alzheimer's brain genomic DNA, leading to a hypothesis that Alzheimer's disease (AD) etiological factors such as aluminum (Al), amyloid beta (Abeta) peptide, and Tau might play a role in modulating DNA topology. In the present study, we investigated the interaction of Al and Abeta with DNA. Our results show that Abeta(1-42) could induce a B --> Psi (Psi) conformational change in pUC 18 supercoiled DNA (scDNA), Abeta(1-16) caused an altered B-form, whereas Al induced a complex B-C-A mixed conformation. Ethidium bromide binding and agarose gel electrophoresis studies revealed that Al uncoiled the DNAto a fully relaxed form, whereas Abeta(1-42) and Abeta(1-16) effected a partial uncoiling and also showed differential sensitivity toward chloroquine-induced topoisomer separation. Our findings show for the first time that Abeta and Al modulate both helicity and superhelicity in scDNA. A new hypothetical model explaining the potential toxicity of Abeta and Al in terms of their DNA binding properties leading to DNA conformational alteration is proposed.