Protection against β-amyloid-induced apoptosis by peptides interacting with β-amyloid

Abstract

β-Amyloid peptide produces apoptosis in neurons at micromolar concentrations, but the mechanism by which β-amyloid exerts its toxic effect is unknown. The normal biological function of β-amyloid is also unknown. We used phage display, coprecipitation, and mass spectrometry to examine the proteinprotein interactions of β-amyloid in normal rabbit brain in order to identify the biochemical receptors for β-amyloid. β-Amyloid was found to bind primarily to proteins involved in low density lipoprotein and cholesterol transport and metabolism, including sortilin, endoplasmic reticulum-Golgi intermediate compartment 2 (ERGIC2), ERGIC-53, steroid 5α-reductase, and apolipoprotein B. β-Amyloid also bound to the C-reactive protein precursor, a protein involved in inflammation, and to 14-3-3, a protein that regulates glycogen synthase kinase-3β, the kinase involved in tau phosphorylation. Of eight synthetic peptides identified as targets of β-amyloid, three were found to be effective blockers of the toxic effect of β-amyloid on cultured neuronal cells. These peptides bound to the hydrophobic region (residues 17-21) or to the nearby protein kinase C pseudo-phosphorylation site (residues 26-30) of β-amyloid, suggesting that these may be the most critical regions for β-amyloid effector action and for aggregation. Peptides or other small molecules that bind to this region may protect against β-amyloid toxic effect by competitively blocking its ability to bind β-amyloid effector proteins such as sortilin and 14-3-3. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.