EVIDENCE OF OXIDATIVE STRESS AND IN-VIVO NEUROTOXICITY OF BETA-AMYLOID IN A TRANSGENIC MOUSE MODEL OF ALZHEIMERS-DISEASE - A CHRONIC OXIDATIVE PARADIGM FOR TESTING ANTIOXIDANT THERAPIES IN-VIVO

Increased expression of antioxidant enzymes and heat-shock proteins ar e key markers of oxidative stress. Such proteins are abnormally presen t within the neuropathological lesions of Alzheimer's disease (AD), su ggesting that oxidative stress may play significant but yet undefined roles in this disorder. To gain further insight into the role of oxida tive stress in AD, we studied the expression of CuZn superoxide dismut ase (SOD) and hemoxygenase-1 (HO-1), two established markers of oxidat ive stress, in a transgenic mouse model of AD. Immunohistochemistry wi th anti-SOD and anti-HO-1 antibodies revealed a very pronounced increa se of these proteins only in aged transgene-positive mice. Interesting ly, the distribution of the oxidative burden was largely overlapping w ith dystrophic neuritic elements in the mice as highlighted with anti- ubiquitin antibodies. Because the most conspicuous alterations were id entified around amyloid (A beta) deposits, our results provide strong support for the hypothesis that A beta is neurotoxic in vivo and that such toxicity is mediated by free radicals. To obtain additional exper imental evidence for such an interpretation (ie, a cause-effect relati onship between A beta and oxidative neurotoxicity), PC12 cells were ex posed to increasing concentrations of A beta or to oxidative stress. I n agreement with the in vivo findings, either treatment caused marked induction of SOD or HO-1 in a dose-dependent fashion. These results va lidate the transgenic approach for the study of oxidative stress in AD and for the evaluation of antioxidant therapies in vivo.