BRAIN AMYLOID - A PHYSICOCHEMICAL PERSPECTIVE

The ability to form stable cross-beta fibrils is an intrinsic physicoc hemical characteristic of the human beta-amyloid peptide (A beta), whi ch forms the brain amyloid of Alzheimer's disease (AD). The high amylo idogenicity and low solubility of this hydrophobic approximate to 40-m er have been barriers to its study in the past, but the availability o f synthetic peptide and new physical methods has enabled many novel ap proaches in recent years. Model systems for A beta aggregation (releva nt to initial nidus formation) and A beta deposition (relevant to plaq ue growth and maturation) in vitro have allowed structure/activity rel ationships and kinetics to be explored quantitatively, and established that these processes are biochemically distinct. Different forms of t ile peptide, with different physicochemical characteristics, are found in vascular and parenchymal amyloid. Various spectroscopic methods ha ve been used to explore the three-dimensional conformation of A beta b oth in solution and in solid phase, and demonstrated that the peptide adopts a different configuration in each state. A significant conforma tional transition is essential to the transformation of A beta from so lution to fibril. These observations suggest new therapeutic targets f or the treatment of AD.