Inhibition of Alzheimer's Amyloidosis by Peptides That Prevent β-Sheet Conformation

Abstract

Amyloid β-peptide (Aβ) is a major fibrillar component of neuritic plaques in Alzheimer's disease (AD) brains and is related to the pathogenesis of the disease. We hypothesized that amyloid formation could be inhibited by peptides homologous to Aβ (position 17-21) with a similar degree of hydrophobicity, but with a very low propensity to adopt a β-sheet conformation by incorporating proline residues (anti-β-sheet peptides or β-sheet inhibitors). An 11-residue peptide with these characteristics binds to Aβ, inhibits Aβ fibril formation and partially disaggregates preformed fibrilsin vitro.Shorter anti-β-sheet peptides and analogs containing D-amino acids are also able to inhibit Aβ fibrillogenesis. The latter are more resistant to proteolytic degradation and may serve as a starting point to design more efficient peptides derivatives to inhibit amyloidogenesis in vivo.