Designed Fluorescent Probes Reveal Interactions between Amyloid- beta (1-40) Peptides and G sub(M1 Gangliosides in Micelles and Lipid Vesicles)

• Published in: Biophysical journal 2010-09, Vol.99 (5), p.1510-1519
• Main Authors: Mikhalyov, I, Olofsson, A, Groebner, G, Johansson, LB-Aa
• Format: Article
• Language: English
• ISSN: 0006-3495
• DOI: 10.1016/j.bpj.2010.06.043

A hallmark of the common Alzheimer's disease (AD) is the pathological conversion of its amphiphatic amyloid- beta (A beta ) peptide into neurotoxic aggregates. In AD patients, these aggregates are often found to be tightly associated with neuronal G sub(M1 ganglioside lipids, suggesting an involvement of G) sub(M)1 not only in aggregate formation but also in neurotoxic events. Significant interactions were found between micelles made of newly synthesized fluorescent G sub(M1 gangliosides labeled in the polar headgroup or the hydrophobic chain and A beta (1-40) peptide labeled with a BODIPY-FL-C1 fluorophore at positions 12 and 26, respectively. From an analysis of energy transfer between the different fluorescence labels and their location in the molecules, we were able to place the A beta peptide inside G) sub(M)1 micelles, close to the hydrophobic-hydrophilic interface. Large unilamellar vesicles composed of a raftlike G sub(M1/bSM/cholesterol lipid composition doped with labeled G) sub(M)1 at various positions also interact with labeled A beta peptide tagged to amino acids 2 or 26. A faster energy transfer was observed from the A beta peptide to bilayers doped with 581/591-BODIPY-C sub(11-G) sub(M)1 in the nonpolar part of the lipid compared with 581/591-BODIPY-C sub(5-G) sub(M)1 residing in the polar headgroup. These data are compatible with a clustering process of G sub(M1 molecules, an effect that not only increases the A beta peptide affinity, but also causes a pronounced A beta peptide penetration deeper into the lipid membrane; all these factors are potentially involved in A beta peptide aggregate formation due to an altered ganglioside metabolism found in AD patients.)