Based on the fact that genesis of A-beta derived from amyloidogenic processing of APP is a key event in Alzheimer's pathogenesis including inflammation, and that cholesterol homeostasis and cholinergic system regulate APP processing, current Alzheimer's therapy targets cholinergic enhancement [Tacrine, Aricept/Donezepil, Rivastigmine, Galantamine]; and regulation of inflammation by NSAIDs [Aspirin, Ibuprofen, Indomethacin]; COX-2 inhibitors [Celebrex, Vioxx]. These drugs exert serious side effects including gastrointestinal bleeding, liver and renal toxicity, nausea, and are not effective with patients carrying ApoE gene 1. Current investigational drugs include Xanthine derivatives-Propentofylline and cholesterol-lowering agents [HMG-CoA reductase inhibitors-Statins]. Although some statins are shown to be anti-amyloidogenic, few clinical trials with statins are non-conclusive due to their proinflammatory nature/39. In this respect, natural alternative(s) with pleiotropic useful properties and with least adverse effects may provide greater therapeutic benefit over single-ingredient synthetic pharmaceutical drugs having serious side effects. One such alternative is garlic. Aged garlic extract (AGE) contains multipotent phytochemicals. S-Allyl-Cystein (SAC) component of AGE inhibits NFkAPPAB, TNFalpha, IL-1Beta 3, 20, and iNOS/24. Our preliminary data show that AGE reduced TNFalpha and IL-1Beta in Tg2576 in a dose-dependent manner. SAC and Diallyl disulfide (DADS) components of AGE are natural HMG-CoA reductase inhibitors 34/46. Our preliminary data show that AGE reduced cerebral amyloid in AIzheimer's transqenic model (Tg2576). In addition, AGE is known to be free-radical scavenger that enhances anti-oxidant enzymes (SOD, catalase and glutathione reductase) 3, inhibits lipid peroxidation 20, inhibits A-beta-induced apoptosis and improves memory deficits in senescence-accelerated mice. Thus, AGE is a natural """"""""NSAID, Statin, anti-oxidant and anti-apoptotic agent""""""""-a combination of many single-ingredient synthetic pharmaceutical drugs currently used for Alzheimer's therapy. However, the validity of AGE as Alzheimer's therapy has not been explored. This project is to determine pleiotropic effects of AGE in Alzheimer's Swedish double mutant (K670M/N671L) model (Tg2576). Hypothesis: Multi-potent natural alternative AGE will prevent or reverse AD-like pathology and ameliorate behavioral deficits in Tg2576.
Specific Aims : [1] Determine if dietary AGE will promote non-amyloidogenic processing and reduce pre-existing amyloid burden in Tg2576; [2] Determine if dietary AGE will attenuate A-beta-induced inflammatory cascade in Tg2576; [3] Determine if dietary AGE will inhibit apoptosis in Tg2576; [4] Determine if dietary AGE will improve hippocampal-based Morris Water Maze performance in Tg2576. Significance: Current AD-treatment utilizing cholinergic enhancers and NSAIDs is limited due to their adverse side effects and do not modify the disease process. If successful, this project will validate the use of safe, naturally well-tolerated, cost-effective and alternative herbal pharmacotherapy for treating AD.
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