Surface Behavior and Lipid Interaction of Alzheimer -Amyloid Peptide 1-42: a Membrane-disrupting Peptide

¹ CIQUIBIC-CONICET-Departamento de Química Biol&oacutgica, Facultad de Ciencias Químicas
² MEMPHYS - Center for Biomembrane Physics. Departments of Physics
³ School of Chemistry, University of Melbourne
⁴ MEMPHYS - Center for Biomembrane Physics-Biochemistry and Molecular Biology
⁵ FAC. CIENCIAS QUIMICAS, UNIV. NAC. CORDOBA

^* To whom correspondence should be addressed. E-mail: gfidelio{at}dqb.fcq.unc.edu.ar.

Submitted on November 4, 2004
Revised on December 2, 2004
Accepted on 26 January 2005

	Abstract

Amyloid aggregates, found in patients that suffer from Alzheimer's disease, are composed of fibril forming peptides in a -sheet conformation. One of the most abundant components in amyloid aggregates is the beta amyloid peptide 1-42 (A 1-42). Membrane alterations may proceed to cell death by either an oxidative stress mechanism, caused by the peptide and synergized by transition metal ions, or through formation of ion channels by peptide interfacial self-aggregation. Here we demonstrate that Langmuir films of A 1-42, either in pure form or mixed with lipids, develop stable monomolecular arrays with a high surface stability. By using micropipette aspiration technique and confocal microscopy we show that A 1-42 induces a strong membrane destabilization in giant unilamellar vesicles (GUVs) composed of palmitoyloleoylphosphatidylcholine, sphingomyelin and cholesterol, lowering the critical tension of vesicle rupture. Additionally, A 1-42 triggers the induction of a sequential leakage of low and high molecular weight markers trapped inside the GUVs, but preserving the vesicle shape. Consequently, the A 1-42 sequence confers particular molecular properties to the peptide that in turn influence supramolecular properties when is associated to membranes which may result in toxicity, including: i) an ability of the peptide to strongly associate with the membrane, ii) a reduction of lateral membrane cohesive forces, and iii) a capacity to break the transbilayer gradient and puncture sealed vesicles.

Key Words: Alzheimer's disease, giant unilamellar vesicles, lipid-peptide interaction, membrane disruption, micropipette aspiration, peptide monolayers

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