Protection against beta-amyloid-induced apoptosis by peptides interacting with beta-amyloid.
beta-Amyloid peptide produces apoptosis in neurons at micromolar concentrations, but the mechanism by which beta-amyloid exerts its toxic effect is unknown. The normal biological function of beta-amyloid is also unknown. We used phage display, co-precipitation, and mass spectrometry to examine the protein-protein interactions of beta-amyloid in normal rabbit brain in order to identify the biochemical receptors for beta-amyloid. beta-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 5alpha-reductase, and apolipoprotein B. beta-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-3beta, the kinase involved in tau phosphorylation. Of eight synthetic peptides identified as targets of beta-amyloid, three were found to be effective blockers of the toxic effect of beta-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 beta-amyloid, suggesting that these may be the most critical regions for beta-amyloid effector action and for aggregation. Peptides or other small molecules that bind to this region may protect against beta-amyloid toxic effect by competitively blocking its ability to bind beta-amyloid effector proteins such as sortilin and 14-3-3.
Nelson
Thomas J
TJ
Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland 20850, USA. tjnelson@brni-jhu.org
Alkon
Daniel L
DL
D048948:14-3-3 Proteins / Q000378:metabolism; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000032:analysis; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides / Q000502:physiology / Q000633:toxicity*; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D015153:Blotting, Western; D053148:Caspase 3 / Q000032:analysis; D002460:Cell Line; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D037241:Mannose-Binding Lectins / Q000378:metabolism; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000032:analysis; D011233:Precipitin Tests; D011485:Protein Binding; D051381:Rats; D000099183:Sortilin
D048948:14-3-3 Proteins; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D001055:Apolipoproteins B; D053148:Caspase 3; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019151:Peptide Library; D010455:Peptides; D010727:Phosphoric Diester Hydrolases; D000099183:Sortilin; C501458:Lman1 protein, rat