Mitochondrial oxidant signaling in Alzheimer's disease

Departamento de Fisiología, Facultad de Medicina, Valencia, Spain.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 06/2007; 11(2):175-81.
Source: PubMed


The role of free radicals in Alzheimer disease pathophysiology has been appreciated for a long time. Originally, radicals were considered as causative of oxidative damage. More recently their role as signalling molecules in this, as well as in other fields of free radical biology, has been underscored. Mitochondria are both generators and targets of radical damage in aging. In this paper we review evidence that radicals generated in mitochondria in the presence of A beta are signals that trigger both the mitochondrial and the extra-mitochondrial pathways of apoptosis. There are gender specific differences in mitochondrial A beta toxicity: mitochondria from young (but not from old) females appear to be protected. 17-beta Estradiol or phytoestrogens like genistein prevent the formation of oxidants by mitochondria and protect against mitochondrial A beta toxicity. Experiments reported here indicate that phytoestrogens might have a role in the prevention of Alzheimer's disease.

16 Reads
  • Source
    • "Our results are in agreement with this hypothesis because the presence of Aβ in the culture medium promoted ROS production (Fig. 6) together with a decrease of cell viability (Figs 1 and 2). Although the mechanisms by which Aβ increases ROS production are not completely elucidated, it is well known that Aβ interacts with mitochondria (see [36] [37] [38] [39]), eliciting H 2 O 2 production [40]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid-beta (A beta) is the main component of senile plaques, one of the hallmarks of Alzheimer's disease. Our results showed that A beta(25-35) decreased neuronal viability while it increased generation of reactive oxygen species (ROS). Under these circumstances, albumin (BSA) prevented ROS production and neuronal death in a dose- and time-dependent manner. In addition, BSA partially prevented the decrease in the expression of GAP-43, MAP-2, and tubulin, and the phosphorylation of tau protein caused by A beta, suggesting that BSA protects against the loss of plasticity caused by the peptide. Our findings suggest that BSA exerts its protective effect by binding to A beta in an equimolecular way, which prevents heterodimer (A beta-BSA) entry into neurons. In fact, BSA prevented A beta internalization, as shown by confocal immunocytochemistry, suggesting that BSA causes its protective effect by sequestrating A beta, which cannot reach its intracellular targets. This is consistent with the idea that A beta must enter neurons to exert its deleterious effects.
    Journal of Alzheimer's disease: JAD 06/2009; 17(4):795-805. DOI:10.3233/JAD-2009-1093 · 4.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative process associated with oxidative stress. In the past, it was claimed that all neuronal lesions involved in the onset and progression of AD were related to oxidative stress.Today, we know that intracellular amyloid beta (Ab) could play a central role in the pathophysiology of the disease. Ab binds to heme groups in mitochondrial membranes causing electron transport chain impairment and loss of respiratory function. The experimental evidence of such oxidative stress leads to the basis for treatment of AD with antioxidants. Many clinical trials have been developed to clarify whether antioxidants are beneficial in AD treatment. However, the results obtained in no way confirm that antioxidants are an effective AD therapy. More research is necessary to clarify this point.
    10/2011; 1(4):8–14. DOI:10.5530/ax.2011.4.3
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this article is to review the role of mitochondria in the pathogenesis of Alzheimer's disease. Additionally, the effect of gender on the incidence of Alzheimer's disease and the pathophysiological mechanisms involved will be discussed. Mitochondria, in the presence of Alzheimer's amyloid-beta peptide, increase the formation of reactive oxygen species which act both as damaging agents and also as signaling molecules. These radicals, in fact, unleash a mechanism involving the liberation of cytochrome c that leads to neuronal apoptosis. Notably, young females appear protected against the mitochondrial toxicity of amyloid-beta, likely due to the upregulation of antioxidant enzymes which occur in females. Estrogens are responsible for this effect. Overall, the findings support the notion that amyloid-beta causes intracellular toxicity via the increased production of oxidant species. Reactive oxygen species generated by mitochondria act as a signal to start the mitochondrial apoptotic pathway. There is a possibility of prevention, and indirect evidence shows that estrogenic compounds (either endogenous estradiol or phytoestrogens such as genistein) may increase the expression of antioxidant enzymes, leading to a lowering of oxidative stress and thus protection against intracellular toxicity of amyloid-beta peptide. These ideas open up the possibility of using phytoestrogens to prevent the onset of Alzheimer's disease. More studies are required to determine whether estrogens and/or phytoestrogens fulfill these expectations.
    Antioxidants and Redox Signaling 11/2007; 9(10):1677-90. DOI:10.1089/ars.2007.1773 · 7.41 Impact Factor
Show more