How do misfolded peptide aggregates affect neuronal cell membranes?

Mathias Lösche, PhD
Carnegie Mellon University (Pittsburgh, PA)
Year Awarded:
2008
Grant Duration:
April 1, 2008 to March 31, 2010
Disease:
Alzheimer's Disease
Award Amount:
$149,940
Grant Reference ID:
A2008307
Award Type:
Pilot
Award Region:
US Northeastern
Mathias Lösche, PhD

Lipid Bilayer Reorganization by Amyloid-beta Oligomers

Summary

This team will use synthetic models of neuronal cell membranes, to study how ABeta interacts with these membranes. The results of these studies will be insight into the damaging effects of ABeta and how this effect varies with membrane lipid composition.

Details


How do misfolded peptide aggregates interact with lipid membranes? More specifically, how do amyloid-Beta (ABeta) oligomers affect neuronal cell membranes? ABeta is a 40 or 42 amino acids long fragment of the amyloid precursor protein APP which has long been implicated t play a crucial role in the etiology of Alzheimer's Disease (AD) . A progressively larger body of evidence has recently accrued that the toxic form of ABeta is a soluble aggregation of the protein, and that such ABeta 'oligomers' interact strongly with cell membranes. Using novel synthetic membrane models, we have developed suitable experimental tools to address the questions posed above in structural, functional and dynamic terms on the molecular level. In this ADR Pilot Grant award, we will to study the response of such synthetic membranes to ABeta oligomers as a function of membrane composition. We are particularly interested in membrane compositions that mimic the lipid characteristics of neuronal cell membranes in order to investigate whether ABeta oligomers interact with such membranes strongly. The proposed research may have implications for a molecular-scale understanding of the damage that ABeta oligomers inflict on neuronal membranes and may in the long run also help to devise synthetic strategies for the early detection of ABeta oligomers in patient samples. The specific aims of this research are to investigate the interaction of ABeta oligomers with synthetic lipid membranes of well-defined compositions and to correlate the structural, functional and dynamic response of such membranes to ABeta with the aggregation state of the peptide.

Publications

Valincius, G., Heinrich, F., Budvytyte, R., Vanderah D.J., McGillivray, D.J., Sokolov, Y., Hall, J.E., and Losche, M. (2008) Soluble amyloid beta-oligomers affect dielectric membrane properties by bilayer insertion and domain formation: Implications for cell toxicity. Biophys. J. 95, 4845-4861  

McGillivray, D.J., Valincius, G., Heinrich, F., Robertson, J.W.F., Vanderah D.J., Febo-Ayala, W., Ignatjev, I., Losche, M., and Kasianowicz, J.J. (2009) Functional reconstitution of Staphylococcus aureus-hemolysin in tethered bilayer lipid membranes. Biophys. J. 96, 1547-1553  

Knoll, W., Naumann, R., Friedrich, M., Robertson, J.W.F., Losche, M., Heinrich, F., McGillivray, D.J., Schuster, B., Gufler, P.C., Pum, D. and Sleytr, U.B. (2009) Solid supported functional lipid membranes based on monomolecular protein sheet crystals: New concepts for the biomimetic functionalization of solid surfaces. Biointerphases 3, FA125. [PMID:20408662}[link not available]

Heinrich, F., Ng, T., Vanderah D.J., Shekhar, P., Mihailescu, M., Nanda, H., and Losche, M. (2009) A new lipid anchor for sparsely-tethered bilayer lipid membranes. Langmuir 25, 4219-4229.  

Shenoy, S., Moldovan, R., Fitzpatrick, J., Vanderah, D. J., Deserno, M., and Losche, M. (2010) In-plane homogeneity and lipid dynamics in tethered Bilayer Lipid Membranes (tBLMs), Soft Matter 6, 1263-1274. [PMID:nd][link not available]

Cizas, P., Budvytyte, R., Morkuniene, R., Moldovan, R., Broccio, M., Losche, M., Niaura, G., Valincius, G. and Borutaite, V. (2010) Size-dependent neurotoxicity of Beta-amyloid oligomers, Arch. Biochem. Biophys. 496, 84-92.  

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.