Prevention of Alzheimer's Associated Aβ-Aggregation by Rationally Designed Non-Peptidic β-Sheet Ligands

A new concept is introduced for the rational design of β-sheet ligands, which prevent protein aggregation: oligomeric acylated aminopyrazoles with a DAD hydrogen bond pattern complementary to that of a β-sheet efficiently block the solvent-exposed β-sheet portions in Aβ(1–40) and thereby prevent the formation of insoluble protein aggregates. Density gradient centrifugation revealed that, in the initial phase, the size of the Aβ aggregates was efficiently kept between the trimeric and 15meric states, whereas after 5 days an additional high molecular weight fraction appeared. With fluorescence correlation spectros…