α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer's disease

Alzheimer's disease (AD) is characterized by the deposition of beta-sheet-rich, insoluble amyloid beta-peptide (A beta) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these A beta oligomers adopt a nonstandard secondary structure, termed alpha-sheet. These oligomers form in the lag phase of aggregation, when A beta-associated cytotoxicity peaks, en route to forming nontoxic beta-sheet fibrils. De novo-designed alpha-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of A beta, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of alpha-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between alpha-sheet content and toxicity. The designed alpha-sheet peptides are also active in vivo where they inhibit A beta-induced paralysis in a transgenic A beta Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The alpha-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.