Curcumin-based analogs as improved inhibitors of Abeta aggregation

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DESCRIPTION (provided by applicant): The development of Alzheimer Disease (AD) is accompanied by a decrease in neural metabolic activity and loss of synaptic integrity, which are attributed to the formation of amyloid-like plaques beginning in the entorhinal complex and hippocampus, later advancing into the neocortex. These plaques result from extracellular aggregation of a 40 or 42 amino acid hydrophobic peptide called Abeta. Although Abeta is continually produced by individuals of all ages, its aggregation is highly dependent on the concentration of monomeric peptide. Once a critical concentration is reached, Abeta undergoes a transition from alpha-helix/random coil to a beta-sheet configuration, which is primarily responsible for its aggregation and deposition. Current therapies for Alzheimer's disease focus on symptomatic aspects of the clinical pathology and include acetylcholine esterase inhibitors and modulation of NMDA receptor activity. Although these therapies have shown a modest effect on slowing cognitive decline, they have yet to demonstrate any major impact on the progression of the disease. The most encouraging therapies to date focus on preventing Abeta oligomerization or dissolution of pre-formed Abeta fibrils, thereby reducing overall amyloid burden. Numerous studies have described inhibitors that are effective in preventing Abeta aggregation; however, their usefulness has been limited due to toxicity or their inability to cross the blood-brain barrier. Curcumin, a polyphenolic natural product, was recently shown to inhibit the formation of Abeta oligomers in vitro and was reported to cross the blood-brain barrier when injected into the circulation and reduce amyloid plaque burden in vivo. However, curcumin was less effective when added to the diet, due to its limited oral bioavailability. From these exciting new findings, we hypothesize that curcumin presents molecular features making it an excellent lead compound for the development of more effective inhibitors of Abeta aggregation that demonstrate improved bioavailability. To address this hypothesis, we will examine our existing chemical library of curcumin-analogs to identify the molecular features of curcumin that are responsible for inhibition of Abeta peptide oligomerization (Specific Aim 1), measure bioavailability of each analog that proves to be an effective inhibitor (Specific Aim 2), and using the experimental data obtained from Aims 1 and 2, improve upon the efficacy of these chemical analogs using ligand-based drug design (Specific Aim 3).