Tjernberg L O, Näslund J, Lindqvist F, Johansson J, Karlström A R, Thyberg J, Terenius L, Nordstedt C
Department of Clinical Neuroscience, Karolinska Hospital, S-171 76 Stockholm, Sweden.
J Biol Chem. 1996 Apr 12;271(15):8545-8. doi: 10.1074/jbc.271.15.8545.
Polymerization of amyloid beta-peptide (Abeta) into amyloid fibrils is a critical step in the pathogenesis of Alzheimer's disease. Here, we show that peptides incorporating a short Abeta fragment (KLVFF; Abeta16-20) can bind full-length Abeta and prevent its assembly into amyloid fibrils. Through alanine substitution, it was demonstrated that amino acids Lys16, Leu17, and Phe20 are critical for binding to Abeta and inhibition of Abeta fibril formation. A mutant Abeta molecule, in which these residues had been substituted, had a markedly reduced capability of forming amyloid fibrils. The present data suggest that residues Abeta16-20 serve as a binding sequence duringA beta polymerization and fibril formation. Moreover, the present KLVFF peptide may serve as a lead compound for the development of peptide and non-peptide agents aimed at inhibiting Abeta amyloidogenesis in vivo.
淀粉样β肽（Aβ）聚合成淀粉样纤维是阿尔茨海默病发病机制中的关键步骤。在此，我们表明，包含短Aβ片段（KLVFF；Aβ16 - 20）的肽可以结合全长Aβ并阻止其组装成淀粉样纤维。通过丙氨酸替代，证明氨基酸Lys16、Leu17和Phe20对于结合Aβ和抑制Aβ纤维形成至关重要。这些残基被取代的突变Aβ分子形成淀粉样纤维的能力明显降低。目前的数据表明，Aβ16 - 20残基在Aβ聚合和纤维形成过程中作为结合序列。此外，目前的KLVFF肽可能作为开发旨在体内抑制Aβ淀粉样变的肽和非肽药物的先导化合物。
