First Evidence for Helical Transitions in Supercoiled DNA by Amyloid β Peptide (1-42) and Aluminum: A New Insight in Understanding Alzheimer's Disease

Abstract

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.

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

“…Studies also reveal that A␤ enters neurons and is present in their lysosomal system (59), whereas inhibition of its engulfment reduces death of neurons (60). A␤ immunoreactivity has also been found in degenerating neurons in transgenic mice and AD brains (61,62).…”

Sublethal Doses of β-Amyloid Peptide Abrogate DNA-dependent Protein Kinase Activity

“…Importantly, A␤(1-42) immunoreactivity has been found in both the cytosol and nuclei of some degenerating neurons in transgenic mice and AD brains (68,69). Therefore, we asked whether in PC12 cells exogenous A␤(1-42) oligomers, the most neurotoxic A␤ species observed in AD, can enter the nucleus where DNA-PK exerts its DNA repair activity.…”

Thermodynamics of the interaction of aluminum ions with DNA: Implications for the biological function of aluminum

“…The interest in the interactions of metal ions with DNA is firstly stimulated by the importance of metal ions to the function of DNA [1][2][3][4][5][6][7][8][9][10]. Secondly, the interactions of metal ions with DNA play key roles in the molecular mechanisms of metal toxicity affecting living organisms [1].…”