Recent evidence suggests that the primary cause of Alzheimer's disease is the progressive accumulation of neurotpxic oligomeric assemblies of the Abeta 1-42 protein. These neurotoxic oligomeric species are known as ADDLs (Ab-derived diffusible ligands). In Tg2576 AD mice, a transgenic Alzheimer's disease animal model, memory performance declines as ADDL levels increase. Human patients with Alzheimer's disease show a 70-fold elevation in ADDL levels relative to unaffected age-matched controls. ADDLs affect memory by directly interfering with synaptic function, which eventually results in synaptic loss over time. This evidence suggests that small molecule, ADDL-directed therapeutics might prevent ADDL-induced cognitive deficits, and slow or reverse disease progression in humans. This stands in contrast to current FDA-approved drugs, which treat the symptoms and not the underlying cause of Alzheimer's disease. The most promising approach to ADDL-directed therapeutics is to prevent ADDL formation by blocking assembly of the Abeta 1-42 protein. The subject of this proposal is to establish and validate a cascade of primary and secondary chemical screens and screen a representative CNS targeted chemical library to identify small molecules that block ADDL assembly. In Phase I, we propose to develop and validate a homogeneous ADDL assembly blocker screening assay, conduct molecular dynamics simulations to build an ADDL structural model, and carry out pilot screening of a selected small molecule library.
Thesaurus Terms: Alzheimer's disease, amyloid protein, drug discovery /isolation, drug screening /evaluation, neuropharmacologic agent, protein biosynthesis, small molecule cognition disorder, combinatorial chemistry, disease /disorder model, ligand, molecular dynamics, neural degeneration, pathologic process, protein localization, structural model, synapse enzyme linked immunosorbent assay, fluorescence polarization, fluorescence resonance energy transfer, high performance liquid chromatography, laboratory mouse, laboratory rat, mass spectrometry, nanotechnology, western blotting
