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.

Amyloid beta and neuromelanin--toxic or protective molecules? The cellular context makes the difference.

Alzheimer's disease (AD) and Parkinson's disease (PD) share several pathological mechanisms. The parallels between amyloid beta (Abeta) in AD and alpha-synuclein in PD have been discussed in several reports. However, studies of the last few years show that Abeta also shares several important characteristics with neuromelanin (NM), whose role in PD is emerging. First, both molecules accumulate with aging, the greatest risk factor for AD and PD. Second, in spite of their different structures, Abeta and NM have similar characteristics that could also lead to neuroprotection. Metals are required to catalyze their formation and they can bind large amounts of these metals, generating stable complexes and thus playing a protective role against metal toxicity. Moreover, they may be able to remove toxic species such as oligopeptides and excess cytosolic dopamine. Third, both Abeta and NM have been implicated in parallel aspects of the neuronal death that underlies AD and PD, respectively. For example, both molecules can activate microglia, inducing release of toxic factors such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO). A careful analysis of these parallel effects of Abeta and NM, including their seemingly paradoxical ability to participate in both cell death and protection, may lead to an improved understanding of the roles of these molecules in neurodegeneration and also provide insights into possible parallels in the pathological mechanisms underlying AD and PD.

Aluminium in Alzheimer's disease: are we still at a crossroad?

Aluminium, an environmentally abundant non-redox trivalent cation has long been implicated in the pathogenesis of Alzheimer's disease (AD). However, the definite mechanism of aluminium toxicity in AD is not known. Evidence suggests that trace metal homeostasis plays a crucial role in the normal functioning of the brain, and any disturbance in it can exacerbate events associated with AD. The present paper reviews the scientific literature linking aluminium with AD. The focus is on aluminium levels in brain, region-specific and subcellular distribution, its relation to neurofibrillary tangles, amyloid beta, and other metals. A detailed mechanism of the role of aluminium in oxidative stress and cell death is highlighted. The importance of complex speciation chemistry of aluminium in relation to biology has been emphasized. The debatable role of aluminium in AD and the cross-talk between aluminium and genetic susceptibility are also discussed. Finally, it is concluded based on extensive literature that the neurotoxic effects of aluminium are beyond any doubt, and aluminium as a factor in AD cannot be discarded. However, whether aluminium is a sole factor in AD and whether it is a factor in all AD cases still needs to be understood.