Anchoring simulations to experiments: challenges for understanding and treating Alzheimer's disease
- Birgit Strodel (Research Centre Jülich, Germany)
- Philippe Derreumaux (CNRS - IBPC and University Paris Diderot, France)
- Normand Mousseau (Montreal University, Canada)
Amyloid fibrils are formed by normally soluble proteins that assemble into insoluble fibers that are resistant to degradation. Their formation can accompany a number of diseases, such as Alzheimer’s and Parkinson’s, and each disease is characterized by a specific protein or peptide that aggregates. Characterizing the mechanisms of the formation of toxic amyloid aggregates and fibrils from soluble, monomeric peptides is of major importance for the field of amyloid diseases research.[1-3] Insights into this process may provide researchers with possible therapeutic approaches to quantify, halt, reverse or avoid amyloid diseases. It is clear that amyloid deposition is a consequence of amyloidosis; what is uncertain is whether it is a causative agent in its pathogenesis or a secondary event. In recent years, the attention has shifted towards oligomers preceding amyloid formation, and it is now thought that oligomers rather than the fully formed fibrils are the toxic species. [4,5] Furthermore, growing evidence suggests that the cytotoxicity in Alzheimer's disease may be due to multiple causes including membrane disruption and permeation, [6-8] interactions with other amyloid proteins or protein receptors. [9,10].
Challenges involving the simulation of amyloid aggregation are numerous. Direct comparison with experiment is difficult due to the large length and time scales involved in aggregation. Furthermore, little to no direct structural data is available for smaller out-of-equilibrium oligomeric species, as these are difficult to follow and measure experimentally. Leaving aside experiments, it is still challenging to compare results between simulations due to the wide range of potentials and methods used. Considerable progress must still be made for simulations to include real environment effects, such as membranes, metal ions,[13,14] and other proteins including receptors and other amyloid proteins. Furthermore, there are still efforts to be made before simulations can really help to design more efficient drugs against Alzheimer's and other amyloid diseases. [15,16]
Note that two similar CECAM workshops on the slightly more general topic “Protein aggregation” took place in 2006 (organized by two of the three current organizers) and 2009. The field has undergone significant development since then, benefiting from improved software and ever larger computers. It is high time to again gather the main players in the field and assess the current state of knowledge and prepare to solve the next generation of questions.
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