INHIBITION OF ALZHEIMERS AMYLOIDOSIS BY PEPTIDES THAT PREVENT BETA-SHEET CONFORMATION

Amyloid beta-peptide (A beta) is a major fibrillar component of neurit ic plaques in Alzheimer's disease (AD) brains and is related to the pa thogenesis of the disease. We hypothesized that amyloid formation coul d be inhibited by peptides homologous to A beta (position 17-21) with a similar degree of hydrophobicity, but with a very low propensity to adopt a beta-sheet conformation by incorporating proline residues (ant i-beta-sheet peptides or beta-sheet inhibitors). An 11-residue peptide with these characteristics binds to A beta, inhibits A beta fibril fo rmation and partially disaggregates preformed fibrils in vitro. Shorte r anti-beta-sheet peptides and analogs containing D-amino acids are al so able to inhibit A beta fibrillogenesis. The latter are more resista nt to proteolytic degradation and may serve as a starting point to des ign more efficient peptides derivatives to inhibit amyloidogenesis in vivo. (C) 1996 Academic Press, Inc.