Structural and mechanistic studies of amyloids related to Alzheimer's disease and Parkinson's disease using engineered binding proteins

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The oligomerization and aggregation of the Alzheimer Aß peptide (Aß) resulting in amyloid plaque formation has been implicated as a key step in Alzheimer s disease (AD) pathogenesis. Consequently, anti-amyloid approaches, which target the production, aggregation and clearance of Aß, constitute the focus of current efforts to develop AD therapeutics. The goal of the present proposal is to support such approaches by providing insight into the molecular aspects of Aß oligomerization, fibril formation, and disaggregation. The suggested research project takes advantage of an engineered binding protein (affibody) which is capable of stabilizing monomeric Aß. First, the Aß-specific affibody will be employed to investigate the equilibria and transitions between the monomeric and the disease-related oligomeric and fibrillar states of Aß (i) in the test tube by NMR spectroscopy, and (ii) in a fly model of AD. Second, the NMR structures of the affibody complexes of the particularly toxic Aß(1- 42) and arctic variants of Aß will be compared with the previously determined complex structure of Aß(1-40) in order to identify potential differences in the conformational preferences of the peptides. Third, the interaction of the protein a-synuclein, which forms amyloid linked to Parkinson s disease, with an a-synucleinspecific affibody will be characterized biophysically and structurally. Potential similarities with the Aß-specific affibody would elucidate commonalities of amyloidogenic proteins and might suggest a general therapeutic approach towards amyloid diseases.