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Background

Several lines of evidence suggest a central role of amyloid-β-peptide (Aβ) in the pathogenesis of Alzheimer's disease (AD). More than Aβ fibrils, small soluble and prion-like propagating Aβ oligomers are suspected to be the major toxic species responsible for disease development and progression. Therefore, eradication of these Aβ oligomers is our principal objective for therapy of AD. Previously, we have identified the fully D-enantiomeric peptide D3 by mirror image phage display selection and showed that it was able to specifically eliminate Aβ oligomers and convert them into non-toxic species. D3 was able to reduce plaque load in transgenic AD mouse models, and improved cognition even after oral application [1]. More recently, we developed derivatives of D3 with improved properties during a lead optimization strategy that focused primarily on the Aβ oligomer elimination efficiency.

Methods

We …