A synthetic peptide corresponding to a region of the human pericentriolar material 1 (PCM-1) protein binds β-amyloid (Aβ1-42 ) oligomers

Abstract

We have recently reported that a ~19-kDa polypeptide, rPK-4, is a protein kinase Cs inhibitor that is 89% homologous to the 1171-1323 amino acid region of the 228-kDa human pericentriolar material-1 (PCM-1) protein (Chakravarthy et al. 2012). We have now discovered that rPK-4 binds oligomeric amyloid-β peptide (Aβ)1-42 with high affinity. Most importantly, a PCM-1-selective antibody co-precipitated Aβ and amyloid β precursor protein (AβPP) from cerebral cortices and hippocampi from AD (Alzheimer's disease) transgenic mice that produce human AβPP and Aβ1-42 , suggesting that PCM-1 may interact with amyloid precursor protein/Aβ in vivo. We have identified rPK-4's Aβ-binding domain using a set of overlapping synthetic peptides. We have found with ELISA, dot-blot, and polyacrylamide gel electrophoresis techniques that a ~ 5 kDa synthetic peptide, amyloid binding peptide (ABP)-p4-5 binds Aβ1-42 at nM levels. Most importantly, ABP-p4-5, like rPK-4, appears to preferentially bind Aβ1-42 oligomers, believed to be the toxic AD-drivers. As expected from these observations, ABP-p4-5 prevented Aβ1-42 from killing human SH-SY5Y neuroblastoma cells via apoptosis. These findings indicate that ABP-p4-5 is a possible candidate therapeutic for AD.

Keywords: Alzheimer's disease; Aβ-binding peptides; Aβ1-42 oligomers; PCM-1 protein.