Development of Small Molecule Therapeutic Agents for the Treatment of Alzheimer’s Disease
Feng-I Chu, M .J. Hsieh, C. K. Liu and Ta-Hsien Lin
Institute of Biochemistry , National Yang-Ming university
Alzheimer’s disease is a neurodegenerative disease which leads to progressive dementia and neuronal death. Currently, the pathogenesis of this disease is still not yet clear. The main histopathological hallmarks of Alzheimer’s disease are the senile plaques within the cerebral cortex and the neurofibrillary tangles within the nerve cells. The primary component of senile plaques is a 39-42 amino acid hydrophobic peptide, b-amyloid peptide, which is derived from proteolysis of a much larger membrane-spanning protein known as b-amyloid precursor protein. The b-amyloid peptide is a soluble peptide which can be detected in blood and cerebrospinal fluid. However, under certain environmental condition, it will polymerize at a very slow rate. The aggregation process converts monomeric, soluble b-amyloid peptide to insoluble fibrils that eventually precipitate as amyloid plaques. Recent studies have suggested that b-amyloid peptide has neurotoxic properties in the aggregated state. Suppression or prevention of the aggregation of b-amyloid peptide maybe an appropriate therapeutic strategy. Our approach is based on that small molecules that can bind to b-amyloid peptides may interfere with its aggregation. By solving high-resolution three-dimensional structures of the complexes one may obtain detailed information of the interactions between the small molecules and b-amyloid peptides, which can be applied to structure-based rational drug design.