Oxidative stress from endogenous and exogenous oxidants has been implicated as a major determinant of aging and as a causative factor in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The possibility that oxidative neuronal damage might cause neurodegenerative diseases was recently strengthened by the observation that the free radical scavenging enzyme Cu/Zn superoxide dismutase (SOD1) is mutated in some individuals with inherited ALS. This project will utilize neurochemical and histological studies to assess oxidative stress in postmortem brain tissue from normal individuals with aging and patients with neurodegenerative diseases.
The Specific Aims are to: (1) determine whether there is increased oxidative damage to proteins, lipid or DNA, and whether there are altered antioxidant enzyme activities in postmortem brain tissue of individuals with neurodegenerative diseases and normal aging, (2) utilize histological techniques to study oxidative damage in specific populations of neurons vulnerable to the neurodegenerative diseases; (3) determine whether biochemical markers of oxidative damage are increased in plasma and urine of patients with AD, PD and ALS; and (4) develop animal models of oxidative stress using antisense DNA to SOD1 and transgenic mice either oxer-expressing mutant forms of SOD1 or with targeted inactivation of SOD1. The proposed studies will provide a direct assessment of markers of oxidative stress in postmortem tissue in normal individuals with aging and in AD, PD and ALS patients. The combined neurochemical and histological studies will characterize the nature and distribution of the oxidative injury at the cellular level. Moreover, our studies will allow development of reliable markers for oxidative stress in both plasma and urine of patients with neurodegenerative diseases. Such markers may be useful both for diagnostic purposed and for monitoring both disease progression and the effects of therapy. Lastly, the animal models we propose to develop should be powerful tools both for studying the biochemical and molecular pathophysiology of oxidative neuronal toxicity and for trials of new therapies.
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