title: Site-specific effects of peptide lipidation on beta-amyloid aggregation and cytotoxicity.
abstract: Beta-amyloid (Abeta) aggregates at low concentrations in vivo, and this may involve covalently modified forms of these peptides. Modification of Abeta 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 Abeta at each of its amino groups using a chemically simpler, close analogue of 4-HNE, the octanoyl group: K16-octanoic acid (OA)-Abeta, K28-OA-Abeta, and Nalpha-OA-Abeta. Octanoylation of these sites on Abeta-(1-40) had strikingly different effects on fibril formation. K16-OA-Abeta and K28-OA-Abeta, but not Nalpha-OA-Abeta, had increased propensity to aggregate. The type of aggregate (electron microscopic appearance) differed with the site of modification. The ability of octanoyl-Abeta peptides to cross-seed solutions of Abeta was the inverse of their ability to form fibrils on their own (i.e. Abeta approximately Nalpha-OA-Abeta>>K16-OA-Abeta>>K28-OA-Abeta). By CD spectroscopy, K16-OA-Abeta and K28-OA-Abeta had increased beta-sheet propensity compared with Abeta-(1-40) or Nalpha-OA-Abeta. K16-OA-Abeta and K28-OA-Abeta were more amphiphilic than Abeta-(1-40) or Nalpha-OA-Abeta, as shown by lower "critical micelle concentrations" and higher monolayer collapse pressures. Finally, K16-OA-Abeta and K28-OA-Abeta are much more cytotoxic to N2A cells than Abeta-(1-40) or Nalpha-OA-Abeta. The greater cytotoxicity of K16-OA-Abeta and K28-OA-Abeta may reflect their greater amphiphilicity. We conclude that lipidation can make Abeta more prone to aggregation and more cytotoxic, but these effects are highly site-specific.
authors: Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
authors: Isam M
authors: IM
authors: Qahwash
authors: Adrienne
authors: A
authors: Boire
authors: Jennifer
authors: J
authors: Lanning
authors: Thomas
authors: T
authors: Krausz
authors: Peter
authors: P
authors: Pytel
authors: Stephen C
authors: SC
authors: Meredith
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D002210:Caprylates / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011499:Protein Processing, Post-Translational
chemical_list: D000447:Aldehydes; D000682:Amyloid; D016229:Amyloid beta-Peptides; D002210:Caprylates; D008823:Micelles; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C027576:4-hydroxy-2-nonenal; C031492:octanoic acid