Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the leading cause of dementia. It currently affects over five million Americans, and incurs an estimated $150 billion total annual costs to Federal and State Government and Business. Its pathogenesis has been related to the accumulation of amyloid beta (AB) protein in the brain. Several recent lines of evidence strongly support the idea that small soluble AB oligomers, rather than fibrillar aggregates, are the actual neurotoxic species, but their precise mode of action remains unknown. This research proposal operates under the hypothesis that Ap oligomers adsorb onto cell membranes and thereby interfer with their normal biological function, e.g. electrical insulation. Our long-term objective is to understand Ap-membrane interactions and relate them to AD etiology. In the present research project computational techniques and models will be developed with the aim to obtain structural information about AB distribution, uncover their cooperative mode of interaction with the membrane, and aid the interpretation of experimental results from the partner projects. The large length- and time-scales involved in AB aggregation require a coarse-grained simulation approach, but a quantitative link calls for the incorporation of finer scale detail. Our rationale for a successful research will therefore be designed around multiscaling methods. Specifically, we aim to (i) re-introduce chemical detail into our coarse-grained membrane model, (ii) Combine an existing CG peptide model with our improved CGIS bilayer model and thereby quantitatively study the interaction of AB peptides with membranes, and (iii) study the large-scale cooperative aggregation of AP oligomers on membranes and their back effect on the molecular organization of the bilayer.
These aims will benefit strongly from a tight cooperation and a frequent knowledge transfer with experimentally working colleagues in this PPG by offering a comparison with data measured in neutron reflectometry, fluorescence cross-correlation spectroscopy, electrophysiology and impedance spectroscopy. Tools developed Within this PPG are thus collectively optimized. In the long term this research will contribute to an understanding of the molecular basis of AD. It helps to identify new drug targets that might prevent the detrimental molecular processes long before noticeable symptoms materialize, thereby enabling possibilities of a timely treatment.
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