Alzheimer's disease (AD) represents an insidious, progressive, neurodestructive process of the human brain clinically characterized by the deterioration of memory and higher cognitive function. Familial AD and the more prevalent sporadic AD share final common neuropathological features that include a presenilin-1 (PS1) mediated catabolism of b-amyloid precursor protein (BAPP) generating neurotoxic amyloid-beta (AB) peptides that are deposited as insoluble senile plaque (SP). AB peptides and SPs increase reactive oxygen species (ROS) production which, in turn, fuel the expression of brain genes that promote proinflammatory (PI) episodes and brain cell death. The appearance in both familial and sporadic AD brain of reactive astrocytes, activated microglia and PI cytokines such as interleukin-1 beta (IL-1 beta) associated with AB and SP suggests that AD brain may be in a chronic state of inflammation. Abundant data that NSAIDs may be effective in ameliorating AD progression further supports a PI component to AD etiopathology. The goal of this project is to clarify the contributions of two key PI gene signaling pathways in AD brain which culminate in excessive stimulation of the neuroinflammatory response: (a) the inducible oxidoreductase cyclooxygenase-2 (COX-2) gene, which encodes the prostaglandin synthase responsible for prostanoid and other PI mediator production and (b) the presenilin-1 (PS1) gene, which drives aberrant processing of BAPP to accelerate AB production, Inducible COX-2 and PS1 gene over expression can both be regarded as upstream PI signaling events centrally involved in AD pathophysiology. The generation of ROS by AB also activates the binding to promoter DNA of NF-kB, a potent PI transcription factor (TF). Thus, NF-kB-DNA binding, driving COX-2 and PS1 gene transcription represent pivotal activating forces for PI signaling. The COX-2 and PS1 genes (a) exhibit down-regulation during human brain development, (b) are both sharply up-regulated in AD hippocampus, (c) are co-induced by AB42+ IL-I beta] in cultured human brain cells and (d) share at least 9 DNA regulatory motifs in their immediate promoters, including multiple AP1-, HIF1-, NF-Kb and STAT1-DNA binding sites, suggesting correlated gene activation. Using human control and AD brain analysis, human neural cells in primary culture and COX-2- and PS1-promoter, luciferase-reporter transfection models, we propose to test the hypothesis that signaling factors including PI TFs are key in the control of COX-2-and PS1-transcription-mediated over-stimulation of PI pathways that fuel neuronal cell degeneration in AD brain.
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