Journal of Alzheimer’s Disease 11 (2007) 175–181 175 IOS Press Mitochondrial Oxidant Signalling in Alzheimer’s Disease Jose Vi ˜ na * , Ana Lloret, Soraya L. Vall´ es, Consuelo Borr ´ as 1 , Mari-Carmen Bad´ ıa, Federico V. Pallard´ o, Juan Sastre and Maria-Dolores Alonso 2 Departamento de Fisiolog´ ıa, Facultad de Medicina, Valencia, Spain Abstract. 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 Aβ are signals that trigger both the mitochondrial and the extra-mitochondrial pathways of apoptosis. There are gender specific differences in mitochondrial Aβ toxicity: mitochondria from young (but not from old) females appear to be protected. 17-β Estradiol or phytoestrogens like genistein prevent the formation of oxidants by mitochondria and protect against mitochondrial Aβ toxicity. Experiments reported here indicate that phytoestrogens might have a role in the prevention of Alzheimer’s disease. Keywords: Apoptosis, gender, estrogenic compounds, antioxidants, MAP kinases INTRODUCTION Alzheimer’s disease, which is the most common age- related neurodegenerative disorder, is manifested by a progressive loss of memory and cognition. In terms of neuropathology, it is characterized by the accumu- lation of extracellular plaques, chiefly composed of an accumulation of amyloid-β (Aβ) and intracellular neu- rofibrillary tangles which consist of aggregates of hyper phosphorylated tau protein. Recently, however, the role of Aβ in Alzheimer’s dis- ease has been centred more on its intracellular toxicity than on the extracellular accumulation as plaques [1]. Indeed, it has been proposed that accumulation as plaques may be more a protective mechanism than a causative pathogenic mechanism of the disease [2]. Aβ 1 Present address. Universidad Cat´ olica de Valencia, Guillem de Castro 94, 46003 Valencia, Spain. 2 Present address. Department of Neurology, Hospital Clinico Universitario, Avenida Blasco Ib´ a˜ nez 17, 46010 Valencia, Spain. ∗ Corresponding author: Dr. Jose Vi˜ na, Departamento de Fisi- olog´ ıa, Facultad de Medicina, Avenida Blasco Ib´ a˜ nez 15, 46010 Va- lencia, Spain. Tel.: +34 963 864 650; Fax: +34 963 864 642; E-mail: jose.vina@uv.es. forms intercellularly and causes a number of cellular lesions which include damage to mitochondria [3] and lysomes [4]. We have observed, as have other laboratories, that Aβ peptide causes an increase in mitochondrial gener- ation of oxidants which leads to oxidative stress, even- tually causing cell degeneration and apoptosis. In fact, the mitochondrial decay in Alzheimer’s disease has been considered as a model of exacerbated ageing. Reactive oxygen species (ROS) not only have a dam- aging effect on cells but, of crucial importance, they are signals which lead to various adaptations to physio- logical stimuli such as physical exercise [5] or to death processes, for instance apoptosis [6]. In this report we re-examine evidence that links ROS signalling with mitochondrial damage causing “death signals” that may lead to neuronal apoptosis. We pro- pose a mechanism for the protection against Aβ toxicity by estradiol or genistein. How ROS Affect Cell Signalling Free radicals, particularly oxygen free radicals and other reactive oxygen species such as H 2 O 2 (which is ISSN 1387-2877/07/$17.00  2007 – IOS Press and the authors. All rights reserved