Oxidative damage is a key feature in the brain of Alzheimer's disease (AD) patients. In one well- studied mouse model of AD, Tg2576 mice that overexpress a double mutant form of amyloid precursor protein (APP), amyloid plaque deposition was shown to be associated with oxidative damage. In addition, these AD model mice exhibited diminished axon transport in vivo, as measured by manganese enhanced magnetic resonance imaging, long-term potentiation (LTP), and impaired hippocampus-dependent memory. We recently have found that scavenging mitochondrial superoxide by overexpression of mitochondrial superoxide dismutase (SOD-2) can prevent the aforementioned abnormalities. Although these are extremely exciting findings, it is not clear how preventing oxidative stress originating from mitochondria can reverse nearly all of the cellular and behavioral phenotypes in the Tg2576 mice. One possibility is that overexpression of SOD-2 prevents increased phosphorylation of the translation initiation factor eIF2?. Phosphorylation of eIF2? results in an inhibition of general protein synthesis, and it was shown recently that eIF2? phosphorylation is elevated in the hippocampus of Tg2576 mice. Importantly, it also was shown that the increased eIF2? phosphorylation exhibited by the Tg2576 mice could be prevented by the anti-oxidant vitamin E. Therefore, we examined the levels of eIF2? phosphorylation in Tg2576 mice that were crossed with the transgenic mice that overexpress SOD-2. Our preliminary data indicate that overexpression of SOD-2 prevents the increased eIF2? phosphorylation in the brains of Tg2576 mice. These exciting preliminary findings have prompted us to hypothesize that preventing increased eIF2? phosphorylation will prevent A?-induced blockade of LTP in vitro and reverse the aforementioned impairments in LTP and hippocampus-dependent memory displayed by the Tg2576 mice in vivo. To test this hypothesis, we will 1) determine whether A?-induced blockade of LTP requires reactive oxygen species (ROS) produced via mitochondria and/or NADPH oxidase, 2) determine whether A? induces ROS-dependent increases in eIF2? phosphorylation via mitochondria and/or NADPH oxidase, 3) determine whether A?-induced blockade of LTP requires eIF2? phosphorylation via PERK, and 4) determine whether genetic reduction of eIF2? phosphorylation prevents impairments in hippocampal LTP and memory displayed by Tg2576 mice. The results of these experiments should provide crucial information concerning whether PERK-eIF2? signaling is a target of oxidative stress in AD. Such information should be useful in developing pharmacological and therapeutic strategies for treatment of not only AD, but also other neurodegenerative diseases that involve oxidative stress and alterations in protein synthesis.
The overall goal of the proposed work in this application is determine the source and mechanisms responsible for oxidative stress-induced impairments in synaptic plasticity and memory in models of Alzheimer's disease, the most common form of dementia in older individuals. It is estimated that 5.2 million people in the United States are living with Alzheimer's disease and 10 million baby boomers will develop the disease in their lifetime. Current costs of Alzheimer's are estimated to be $148 billion per year. We have proposed experiments to determine specific targets of oxidative stress that impact protein synthesis, and will use pharmacological and genetic approaches to reverse A?-induced impairments in synaptic plasticity in vitro and synaptic plasticity and memory impairments in vivo in mice that model Alzheimer's disease. These studies have the potential to identify several new therapeutic targets for the treatment of Alzheimer's disease.
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