secretase inhibition remains a viable anti-amyloidogenic strategy. In addition to previous reports that novel ?-secretase inhibitors (GSI) significantly reduced Aa production both in vitro and in vivo, Comery and colleagues recently reported that similar GSIs may even improve cognitive functioning in a transgenic mouse model of AD (Tg2576). These finding have functioned to further the vigorous search for potential candidate GSIs. Among the many promising potential candidates are the glycogen synthase kinase 3 (GSK-3) inhibitors. These compounds target this tonically active serine/threonine kinase, which has been implicated in several disorders of the CNS. With regard to Alzheimer's disease (AD), both isoforms of GSK-3 (a and a) have been found to directly phosphorylate tau on residues specific to hyperphosphorylated paired helical filaments (PHF), GSK-3a has been shown to phosphorylate APP and to contribute to Aa mediated neurotoxicity, and GSK-3a has been found to phosphorylate PS1, which may act as a docking site for subsequent tau phosphorylation. Therefore, GSK-3 inhibitors are especially attractive as they may not only oppose Aa generation but also neurofibrillary tangle (NFT) formation. Moreover, Phiel and colleagues reported that inhibition of the GSK-3a isoform may regulate ?-secretase cleavage of APP in a substrate-specific manner. Accordingly, this selective inhibition of GSK-3 might provide the maximal therapeutic benefit while reducing the potential for toxic side-effects. The intense search for small-molecular compounds that may modulate AD pathology has advanced the analysis of specific dietary derived substances from fruits and vegetables, which epidemiological study suggest are beneficial against the neurodegeneration and aging processes. In this light, recent focus has been given to a group of polyphenols categorized as flavonoids, which have been found to be potentially anti-amyloidogenic. In our preliminary studies we demonstrate that treatment of both murine N2a cells transfected with the human "Swedish" mutant form of APP (SweAPP N2a cells) and primary neuronal cells derived from Alzheimer's "Swedish" mutant APP overexpressing mice (Tg2576 line) with the flavonoid luteolin results in a significant reduction in Aa generation. Furthermore, data show that luteolin treatment apparently achieves this reduction through a selective inactivation of the GSK-3a isoform. As in vivo validation, we find that administration of luteolin and a glycoside of a structurally similar flavonoid, diosmin, to Tg2576 mice similarly reduces Aa generation potentially through GSK-3 inhibition. Importantly, this reduction in GSK-3 activation increases phosphorylation of presenilin 1 (PS1), which forms the catalytic core of the ?-secretase complex, and may suggest a mechanism whereby these small-molecular compounds (GSK-3 inhibitors) modulate AD pathology. In this proposal, we will evaluate this small-molecular compound's therapeutic effect on improving cognitive impairment and correlation of this effect with reducing cerebral Aa pathology in a transgenic mouse model of AD via an oral administration. Flavonoid-diosmin (DiosMemTM) will be orally administered to Tg2576 mice before (prophylactic treatment group) or after (therapeutic treatment group) development of AD-like pathology. Groups of untreated non-transgenic littermates will be compared to the transgenic treatment groups. Oral administration of DiosMemTM to Tg2576 mice will be performed for 6 months. Aim 1, following the administration, cognitive testing will be done at several ages. Aim 2, we will sacrifice these mice at several ages to examine histological and biochemical endpoints and correlate pathological changes with improvement of cognitive impairment. In this study, we plan to evaluate two time points comparing DiosMemTM to control. Groups will be compared by their effects on opposing cognitive impairment and reducing AD-like pathology. These studies could lay the foundation for AD clinical trials with DiosMemTM diet supplementation in the near future.
Public Health Relevance: Relevance to public health in this proposal, we will fully characterize the effect of flavonoid-diosmin (DiosMemTM) on being beneficial to cognitive impairment and correlate its therapeutic effect with reducing cerebral amyloidosis in a transgenic mouse model of Alzheimer's disease (AD). These studies will lay the foundation for AD clinical trials with DiosMemTM in the near future.
Public Health Relevance: Project Narrative - Relevance to public health In this proposal, we will fully characterize the effect of flavonoid-diosmin (DiosMemTM) on being beneficial to cognitive impairment and correlate its therapeutic effect with reducing cerebral amyloidosis in a transgenic mouse model of Alzheimer's disease (AD). These studies will lay the foundation for AD clinical trials with DiosMemTM in the near future.
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