Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer’s disease M.E. De Leo a, *, S. Borrello a , M. Passantino a , B. Palazzotti a , A. Mordente b , A. Daniele c , V. Filippini c , T. Galeotti a , C. Masullo c a Institute of General Pathology, Catholic University, School of Medicine, Largo F. Vito, 1-00168 Rome, Italy b Institute of Biological Chemistry, Catholic University, School of Medicine, Largo F. Vito, 1-00168 Rome, Italy c Institute of Neurology, Catholic University, School of Medicine, Largo F. Vito, 1-00168 Rome, Italy Received 6 April 1998; accepted 29 May 1998 Abstract Substantial evidence supports the hypothesis that oxygen free radicals are involved in various neurodegenerative disorders. To assess the presence of oxidative stress in Alzheimer’s disease (AD) we examined the activity of the enzyme copper-zinc superoxide dismutase (CuZnSOD) in red blood cells, the levels of the mitochondrial inducible enzyme manganese superoxide dismutase (MnSOD) mRNA in lymphocytes, and the total radical-trapping antioxidant capacity (TRAP) in plasma of AD patients and in a group of age-matched non-demented controls. We found that CuZnSOD activity (P  0.01 vs. controls) was signifi- cantly increased as well as the MnSOD mRNA levels while the total antioxidant status (P  0.001 vs. controls) was decreased in AD patients. These findings support the role of oxidative alterations in the pathogenetic mechanism underlying AD neuro- degeneration.  1998 Elsevier Science Ireland Ltd. All rights reserved Keywords: Alzheimer’s disease; Oxidative stress; Manganese superoxide dismutase mRNA Recent findings indicate that cellular events involving oxidative stress may be a basic mechanism of neurodegen- erative diseases [2]. In fact reactive oxygen species (ROS) affect neuronal viability and have been also implicated in the pathogenetic mechanism underlying a number of patho- logical conditions of the brain. Oxidative stress can damage critical biological molecules and initiate a cascade of events leading to impaired cellular function or cell death [9]. Mammalian cells possess enzymatic antioxidant defences to cope with oxygen free radicals, e.g. the cytosolic copper- zinc superoxide dismutase (CuZnSOD) and the mitochon- drial manganese superoxide dismutase (MnSOD), which catalyze the dismutation of superoxide anions to hydrogen peroxide. The CuZnSOD gene, mapped on chromosome 21, is sus- pected to be involved in the neuropathology observed in Alzheimer’s disease (AD) [19]. An overproduction of CuZnSOD might increase the rate of dismutation of super- oxide anion radical to hydrogen peroxide that may give rise to the cytotoxic hydroxyl radical (HO • ). This oxygen spe- cies, highly reactive, is considered the radical most likely responsible for oxidative damage and DNA modifications. It is known that the CuZnSOD is a constitutive enzyme in human cells, while the MnSOD is up-regulated under oxi- dative toxicity or inducers such as LPS, TNF-a, IL-1, IL-6 and PMA [6,16]. Moreover recent findings indicate that amyloid beta-pep- tide (Ab) can be neurotoxic by mechanisms involving the generation of H 2 O 2 , ROS and lipid peroxidation [18], the alteration of mitochondrial function and the loss of calcium homeostasis [12]. An increase in ROS production could be also related to an elevated iron and aluminium content in the brain of AD patients [5,20]. We have investigated some factors involved in antioxi- dant protection, such as the enzymatic activity of the cyto- solic CuZnSOD in AD erythrocytes, the levels of the mitochondrial enzyme MnSOD mRNA in AD lymphocytes Neuroscience Letters 250 (1998) 173–176 0304-3940/98/$19.00  1998 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940(98)00469-8 * Corresponding author. Tel.: +39 6 30154914; fax: +39 6 3386446.