Oxidative stress is an important pathogenic mechanism of Alzheimer's disease (AD) and related disorders. The accumulation of beta-amyloid (Abeta) deposits in the brain in AD is a key initiator of amyloid plaques resulting in neuronal damage and dysfunction and microglial activation. Abeta perturbs cellular properties mainly by oxidant stress, which overwhelms the cellular antioxidant defense mechanisms. Recent studies suggest that engagement of the Receptor for Advanced Glycation Endproducts (RAGE) with Abeta peptide perturbs cellular functions resulting in oxidant stress, sustained activation of the transcription factor NF-kappaB and cell death. We hypothesize that Abeta amyloid results from interaction of Abeta peptide with RAGE, which facilitates Abeta deposition and exacerbates cellular perturbation by activation of cellular RAGE. The focus of this proposal is to understand the function of RAGE in the oxidative stress associated with AD.
The first aim of this proposal is to understand the function of RAE in the oxidative stress associated with AD.
The first aim of this proposal will determine if RAGE is necessary and sufficient for oxidative stress induced by Abeta. This will be accomplished using neuronal cell lines expressing wildtype and dominant-negative RAGE.
The second aim will determine if APP/PS-1 knockin mice with targeted expression or disruption of RAGE display altered Amyloid deposition and oxidative stress.
The third aim will determine the effect of mice expressing the APP/PS-1 mutations and a dominant-negative form of RAGE on amyloid deposition and neuronal oxidative stress.
The final aim will determine the expression of oxidative stress markers in the AD brain and co-localization with RAGE. The long-term goal of this proposal is to understand the role of RAGE in oxidative stress in order to determine if antagonism of the Abeta/RAGE interaction is a potential therapeutic strategy for individuals with AD.
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