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Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):8895-8900. doi: 10.1073/pnas.1820585116. Epub 2019 Apr 19.

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

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Department of Molecular Engineering, University of Washington, Seattle, WA 98195.
Department of Bioengineering, University of Washington, Seattle, WA 98195.
Department of Chemistry, University of Washington, Seattle, WA 98195.
Department of Integrative Physiology, University of Colorado, Boulder, CO 80309.
Redshift BioAnalytics, Burlington, MA 01803.
Roskamp Institute, Sarasota, FL 34243.
Department of Molecular Engineering, University of Washington, Seattle, WA 98195;


Alzheimer's disease (AD) is characterized by the deposition of β-sheet-rich, insoluble amyloid β-peptide (Aβ) 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 Aβ oligomers adopt a nonstandard secondary structure, termed "α-sheet." These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, 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 α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.


Alzheimer’s disease; amyloid beta; soluble oligomer binding assay; toxic soluble oligomers; α-sheet

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