Effects of Hyperoxia in Alzheimer’s Transgenic Mice

An association between major surgery in the elderly and precipitation of Alzheimer’s disease (AD) has been reported. Hyperoxia (100%) oxygen is commonly administered after surgery to increase the oxygen content of blood. However, hyperoxia is a potent cerebral vasoconstrictor and generator of free radicals, as is β-amyloid (Aβ). This study was aimed at examining behavioral, neuropathological, and neurochemical effects of hyperoxia treatments in APPsw transgenic mice (Tg+), which have elevated brain Aβ levels by 3-4 months of age but are not yet cognitively-impaired. At 3 months of age, Tg+ mice were pre-tested in the radial arm water maze (RAWM) task of working memory and found to be unimpaired. At 4.5 months of age, half of the Tg+ mice received the first of 3 equally-spaced hyperoxia sessions (3 hrs each) given over the ensuing 3 months. The other half of the Tg+ mice were exposed to compressed air during these 3 sessions. RAWM testing performed immediately following the final gas session at 7.5 months of age revealed significant working memory impairment in Tg+ mice exposed to hyperoxia. The Tg+ group that was exposed to placebo treatment showed a trend towards impairment, however, was not significantly different from the non-transgenic group. Hyperoxia-induced memory impairment in Tg+ mice did not involve changes in brain Aβ deposition, degenerative cell numbers in hippocampus, neocortical lipid peroxidation, or hippocampal levels of APP, ApoE, COX-2, or GFAP. The combination of excess Aβ and hyperoxia could have induced greater oxidative stress and cerebral vasoconstriction than either one alone, resulting in a pathologic cerebral hypoperfusion that triggered subsequent cognitive impairment. These results suggest that humans genetically pre-disposed to AD and those with increased brain Aβ levels have increased risk of developing cognitive impairment following hyperoxia treatment and cast doubt on the wide spread use of hyperoxia in aged individuals at risk for developing AD