Increasing evidence points to a causative role for amyloid-beta peptide (Afi) in the pathogenesis of Alzheimer disease (AD). Impaired memory, synaptic loss and mitochondria! dysfunction occur prior to extensive extracellular deposition of amyloid in brains of AD-type murine models, and in AD patients, suggesting that early in the disease process, when levels of pathogenic Afi are low, mechanisms amplifying and focusing the effects of Afi on vulnerable cellular targets could contribute critically to cellular dysfunction. RAGE (Receptor for Advanced Glycation Endproducts), a multiligand receptor of the immunoglobulin superfamily, functions as a signal transducing cell surface acceptor site for amyloid-beta peptide (Afi). Results generated during the past grant period support a link between RAGE and Afi- mediated neuronal stress and synaptic dysfunction relevant to AD. Interaction of RAGE with Afi causes accelerated spatial learning/memory deficits and synaptic dysfunction, and more prominent neuropathologic changes as evidenced by observations in double transgenic mice (Tg) pverexpressing mutant amyloid precursor protein (Tg mAPP) and RAGE in neurons before the steep rise in cerebral Afi and plaque formation occur. Treatment of Tg mAPP mice with soluble RAGE (sRAGE) prevented impaired behavioral function and decreased deposit of Afi in brain parenchyma. These data indicate that increased RAGE in an Afi-rich environment (AD brain and Tg mAPP mice) promotes neuronal stress, as reflected by neuronal dysfunction in the early stages of AD. We hypothesize that blockade of RAGE will attenuate All- mediated cellular perturbation. We will address this hypothesis using RAGE knockout mice and transgenic mice expressing signal transduction deficient mutants of RAGE in which the cytosolic domain of the receptor has been deleted, thereby imparting a dominant negative or DN-RAGE effect, in neurons and microglia.. The goal of this project is to gain insights into the role of RAGE in Ad-induced neuronal and microglial stress, focusing on signal transduction, synaptic function, and neuroinflammation, utilizing novel genetically manipulated transgenic mouse models (Tg DN-RAGE and RAGE null mice). If our studies in RAGE/RAGE signaling mutant display protection upon by breeding into the Tg mAPP background, then such findings will provide further substantial support for targeting RAGE as a key therapeutic strategy in AD. This Project is critically linked to Project 2 of this Program. As antagonism of RAGE nears clinical trials in Alzheimer's Disease and diabetes, it is imperative to dissect the beneficial/maladaptive impact of RAGE in both the CMS and PNS, and, as well, in chronic stress and in the setting of superimposed acute injury. Projects 1 and 2 are uniquely positioned to address these questions due to the long-time collaboration of the Project leaders. Project 1 will also work closely with Projects 3-4 on the role of Afi- mediated cell stress in the CMS. Collaborative interactions include: exchange of reagents/techniques related to RAGE biology (Project 2), evaluation of cellular stress (Projects 3-4), and, generation of Tg mice (core B), behavioral and neuropathologic analysis (Core C).
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