Review: Modulating factors in amyloid-beta fibril formation

Amyloid formation is a key pathological feature of Alzheimer's disease and is considered to be a major contributing factor to neurodegeneration and cl inical dementia. Amyloid is found as both diffuse and senile plaques in the parenchyma of the brain and is composed primarily of the 40- to 42-residue amyloid-beta (A beta) peptides. The characteristic amyloid fiber exhibits a high beta-sheet content and may be generated in vitro by the nucleation-d ependent self-association of the A beta peptide and an associated conformat ional transition from random to beta-conformation. Growth of the fibrils oc curs by assembly of the A beta seeds into intermediate protofibrils, which in turn self-associate to form mature fibers. This multistep process may be influenced at various stages by factors that either promote or inhibit A b eta fiber formation and aggregation. Identification of these factors and un derstanding the driving forces behind these interactions as well as the str uctural motifs necessary for these interactions will help to elucidate pote ntial sites that may be targeted to prevent amyloid formation and its assoc iated toxicity. This review will discuss some of the modulating factors tha t have been identified to date and their role in fibrillogenesis. (C) 2000 Academic Press.