Biophysics Approaches to Study Molecular Mechanism of Alzheimer's Disease: Towards Prevention and Cure | Shull Wollan Center
Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by dementia and memory loss for which no cure or prevention is available. Amyloid toxicity is a result of the non-specific interaction of toxic amyloid oligomers with the plasma membrane.
We use nanoscale biophysics approaches such as atomic force microscopy (AFM), Kelvin probe force microscopy (KPFM), molecular dynamics (MD) simulations and surface plasmon resonance (SPR) to study amyloid aggregation and interaction of amyloid beta (1-42) peptide with lipid membrane. With AFM-based atomic force spectroscopy (AFS), we measured the binging forces between two single amyloid peptide molecules. Using AFM imaging we showed that oligomer and fibril formation is affected by surfaces, presence of metals and inhibitors. We demonstrated that lipid membrane plays an active role in amyloid binding and toxicity. Effect of lipid composition, the presence of cholesterol and melatonin are discussed. We discovered that membrane cholesterol creates nanoscale electrostatic domains which induce preferential binding of amyloid peptide, while membrane melatonin reduces amyloid-membrane interactions, protecting the membrane from amyloid attack. Using AFS we tested a set of novel pseudo-peptide inhibitors (potential drug candidates) and showed that they effectively prevent amyloid-amyloid binding on a single molecule level, and work well in cellular models to prevent amyloid toxicity. These findings contribute to better understanding of the molecular mechanisms of Alzheimer's disease and aid to the developments of novel strategies for cure and prevention of AD.
- M.Robinson, B.Y.Lee, Z.Leonenko, Drugs and Drug Delivery Systems Targeting Amyloid-β in Alzheimer’s Disease. AIMS Molecular Science, 2015, 2(3): 332-358.
- E.Drolle, R.M.Gaikwad, Z.Leonenko, Nanoscale electrostatic domains in cholesterol-laden lipid membranes create a target for amyloid binding. Biophysical Journal, 2012, 103(4), L27-L29.
- F.Hane, E.Drolle, R.Gaikwad, E.Faught, Z.Leonenko. 2011. Amyloid-β aggregation on model lipid membranes: an atomic force microscopy study. J. Alzheimer’s Dis. 26: 485-494.
- E.Drolle, F.Hane, B.Lee, Z.Leonenko, Atomic force microscopy to study molecular mechanisms of amyloid fibril formation and toxicity in Alzheimer’s disease. Journal of Drug Metabolism Reviews, 2014, 46(2): 207-223.
- E.Drolle, N. Kučerka, M.I.Hoopes, Y.Choi, J. Katsaras, M. Karttunen, Z.Leonenko, Effect of melatonin and cholesterol on the structure of DOPC and DPPC membranes, Biochimica & Biophysica Acta: Biomembranes, 2013, 1828 (9): 2247-2254.
- F.T.Hane, S.J.Attwood, Z.Leonenko. Comparison of three competing dynamic force spectroscopy models to study binding forces of Amyloid-β 1-42. Soft Matter, 2014, 10(1): 206-213.
- F.T. Hane, B.Y. Lee, A.Petoyan, A.Rauk, Z.Leonenko, Testing Synthetic Amyloid-β Aggregation Inhibitor Using Single Molecule Atomic Force Spectroscopy. Journal of Biosensors and Bioelectronics, 2014, 54, 492–498.
Dr. Zoya Leonenko, Professor, Department of Physics and Astronomy, Department of Biology, Waterloo Institute for Nanotechnology, University of Waterloo; Vice President of the Biophysical Society of Canada. PhD in Chemical Physics, 1996, Novosibirsk, Russian Academy of Sciences. Dr. Leonenko is leading the Nanoscale Biophysics research group at the University of Waterloo. Current research interests include: biophysics of lipid membrane and lipid-protein interactions, the role of structural changes and physical properties of lipid template in controlling biological processes and diseases; biomedical nanotechnology and quantum biology. Current research projects are: molecular mechanism of Alzheimer’s disease; antimicrobial peptide function; the structure and function of lung surfactant; drug and drug delivery systems development; novel nano-biosensing approaches; quantum effects in neuronal networks.