Alzheimer's Disease Drugs

DESCRIPTION (provided by applicant): Brain accumulation of amyloid-2 (A2) and chronic brain inflammation are both recognized factors in the pathophysiology of Alzheimer's disease (AD). Brain inflammation primarily involves microglial cells. The neural toxi city of A2 is microglia-mediated and involves signaling through transcription factor NF:B. Limiting the activation of NF:B in microglia may be a promising approach to the development of therapies for AD. This translational proposal will focus on in vivo st udies of the natural product resveratrol and some of its analogs. The polyphenol resveratrol exhibits numerous biological activities. Resveratrol also inhibits activation of NF:B. In initial studies of analogs of resveratrol, it was demonstrated that some of these analogs are potent inhibitors of LPS-induced expression of COX-2 and pro-inflammatory cytokines IL12 and IL6 in microglial cells. The expression of these genes is dependent on NF:B activation. The Specific Aim of this phase 1 proposal, which is a proof of principle in vivo study: To examine resveratrol and analogs for their abilities to prevent microglial activation and to reduce A2 plaque burden in the Tg2576 transgenic mouse model of human AD. The most thoroughly examined animal model of AD is th e human APP-Swedish mutation transgenic Tg2576. Between 10-16 months of age, these mice develop substantial A2-amyloid burden with increased microglial density and activation in plaque-forming areas of the brain. This animal model has been used in several prior studies examining the effects of anti-inflammatory compounds on the prevention of microglial activation and A2 peptide deposition. Because of the established association between inflammation and AD pathogenesis, this model will be used to test the mo st promising resveratrol-based analogs. PUBLIC HEALTH RELEVANCE: During the development of Alzheimer's disease, there is overproduction or impaired clearance of a peptide named amyloid-2 (A2), which contributes to the chronic brain inflammation that is com monly found in Alzheimer's disease (AD). Brain inflammation primarily involves cells of the immune system called microglial cells. The neural toxicity of A2 is microglia-mediated and involves a protein called transcription factor NF:B, which regulates many important inflammation factors. Development of an inflammatory state in microglia is an early event in the etiology of AD. Limiting the activation of NF:B in microglia may be a promising approach to the development of therapies for AD. The natural product resveratrol, which is abundant in red wine, inhibits activation of NF:B. Versatile schemes to synthesize analogs of resveratrol have been developed. The Specific Aim of this proposal is to test resveratrol and analogs in an animal model of Alzheimer's dis ease.