The Complexity of Aluminum-DNA Interactions: Relevance to Alzheimer’s and Other Neurological Diseases

Abstract

The DNA molecule is dynamic and polymorphic in nature. Although the right-handed B-form is the most predominant conformation, non-B-DNA conformations also occur in biological systems, for example, Z-DNA, triple helix, tetraplexes, hairpin, cruciform etc., under various physiological conditions. Extensive studies on handedness and various high-ordered structures were carried out for the oligonucleotides, but little is known about genomic DNA topology with respect to non-Watson-Crick right-handed B-DNA forms, their functional ability and possible implication in pathogenic features in the brain, if any?. Alzheimer's disease (AD) is a complex neurological disorder in which etiological factors are not clearly known, although unproven hypotheses have included head trauma, aluminum toxicity and infectious agents. Studies have shown that there is DNA damage, chromatin condensation, and altered gene expression in AD brain. We, for the ®rst time, showed evidence for the presence of a B-Z intermediate form and Z-DNA conformation in hippocampus region in moderately affected and severely affected AD, respectively. Our group also reported for the ®rst time the role of aluminum in modulating DNA topology in d(GCCCATGGGC), d(CCGGGCCCGG), CCG-repeats, supercoiled DNA and calf thymus genomic DNA. We propose a new hypothesis on the role of Al in neurodegeneration of Alzheimer's disease. The relevance of altered DNA topology in Alzheimer's brain, with reference to altered gene expression, nucleosome organization and assembly, DNA susceptibility to damage and terminal differentiation will be discussed.