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J. Biol. Chem., Vol. 282, Issue 51, 36987-36997, December 21, 2007

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Site-specific Effects of Peptide Lipidation on β-Amyloid Aggregation and Cytotoxicity^*

From the Departments of Pathology, Biochemistry, and Molecular Biology and Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois 60637

β-Amyloid (Aβ) aggregates at low concentrations in vivo, and this may involve covalently modified forms of these peptides. Modification of Aβ by 4-hydroxynonenal (4-HNE) initially increases the hydrophobicity of these peptides and subsequently leads to additional reactions, such as peptide cross-linking. To model these initial events, without confounding effects of subsequent reactions, we modified Aβ at each of its amino groups using a chemically simpler, close analogue of 4-HNE, the octanoyl group: K16-octanoic acid (OA)-Aβ, K28-OA-Aβ, and N-OA-Aβ. Octanoylation of these sites on Aβ-(1–40) had strikingly different effects on fibril formation. K16-OA-Aβ and K28-OA-Aβ, but not N-OA-Aβ, had increased propensity to aggregate. The type of aggregate (electron microscopic appearance) differed with the site of modification. The ability of octanoyl-Aβ peptides to cross-seed solutions of Aβ was the inverse of their ability to form fibrils on their own (i.e. Aβ N-OA-Aβ >> K16-OA-Aβ >> K28-OA-Aβ). By CD spectroscopy, K16-OA-Aβ and K28-OA-Aβ had increased β-sheet propensity compared with Aβ-(1–40) or N-OA-Aβ. K16-OA-Aβ and K28-OA-Aβ were more amphiphilic than Aβ-(1–40) or N-OA-Aβ, as shown by lower "critical micelle concentrations" and higher monolayer collapse pressures. Finally, K16-OA-Aβ and K28-OA-Aβ are much more cytotoxic to N2A cells than Aβ-(1–40) or N-OA-Aβ. The greater cytotoxicity of K16-OA-Aβ and K28-OA-Aβ may reflect their greater amphiphilicity. We conclude that lipidation can make Aβ more prone to aggregation and more cytotoxic, but these effects are highly site-specific.

Received for publication, March 13, 2007 , and in revised form, August 9, 2007.

^* This research was supported by National Institutes of Health Grant RO1 NS042852 and the Alzheimer's Association (IIRG-06-27794). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-702-1267; Fax: 773-834-5251; E-mail: scmeredi{at}uchicago.edu.

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