| First Author | Shea D | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 18 | Pages | 8895-8900 |
| PubMed ID | 31004062 | Mgi Jnum | J:274676 |
| Mgi Id | MGI:6297204 | Doi | 10.1073/pnas.1820585116 |
| Citation | Shea D, et al. (2019) alpha-Sheet secondary structure in amyloid beta-peptide drives aggregation and toxicity in Alzheimer's disease. Proc Natl Acad Sci U S A 116(18):8895-8900 |
| abstractText | Alzheimer's disease (AD) is characterized by the deposition of beta-sheet-rich, insoluble amyloid beta-peptide (Abeta) 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 Abeta oligomers adopt a nonstandard secondary structure, termed "alpha-sheet." These oligomers form in the lag phase of aggregation, when Abeta-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 Abeta, 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 Abeta-induced paralysis in a transgenic Abeta 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. |
