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J. Biol. Chem., Vol. 282, Issue 43, 31238-31249, October 26, 2007

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Protection against -Amyloid-induced Apoptosis by Peptides Interacting with -Amyloid^*

From the Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland 20850

-Amyloid peptide produces apoptosis in neurons at micromolar concentrations, but the mechanism by which -amyloid exerts its toxic effect is unknown. The normal biological function of -amyloid is also unknown. We used phage display, co-precipitation, and mass spectrometry to examine the protein-protein interactions of -amyloid in normal rabbit brain in order to identify the biochemical receptors for -amyloid. -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 5-reductase, and apolipoprotein B. -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-3, the kinase involved in tau phosphorylation. Of eight synthetic peptides identified as targets of -amyloid, three were found to be effective blockers of the toxic effect of -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 -amyloid, suggesting that these may be the most critical regions for -amyloid effector action and for aggregation. Peptides or other small molecules that bind to this region may protect against -amyloid toxic effect by competitively blocking its ability to bind -amyloid effector proteins such as sortilin and 14-3-3.

Received for publication, July 6, 2007 , and in revised form, August 30, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Blanchette Rockefeller Neurosciences Institute, 317 Academic and Research Bldg., 9601 Medical Center Dr., Rockville, MD 20850. E-mail: tjnelson{at}brni-jhu.org.

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