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广东快乐十分害人经历:α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease
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There have been over 400 clinical trials for Alzheimer’s disease, all targeting the monomeric and/or fibrillar forms of the Aβ peptide to curb amyloid burden; however, it is the toxic soluble oligomers that are correlated with disease progression, not mature amyloid. Here we provide evidence that Aβ soluble oligomers adopt a nonstandard secondary structure: α-sheet. This structure forms early in aggregation and is strongly correlated with toxicity. Furthermore, designed de novo α-sheet peptides target the toxic oligomers, inhibiting aggregation and toxicity in vitro in cell-based assays and in vivo in two different animal models. This work challenges the prevailing dogma and sheds light on potential new approaches to the problem.
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.
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Author contributions: D.S., J.Z., G.V., C.D.L., M.M., and V.D. designed research; D.S., C.-C.H., T.M.B., N.P., M.C.C., J.C., C.P.T., L.W., and D.P. performed research; D.S., C.-C.H., T.M.B., N.P., M.C.C., C.P.T., L.W., D.P., C.D.L., M.M., and V.D. analyzed data; and D.S., D.P., G.V., C.D.L., M.M., and V.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820585116/-/DCSupplemental.
Published under the PNAS license.
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- Aβ Forms Toxic Oligomers During the Lag Phase of Aggregation
- Toxic Oligomers Contain α-Sheet Structure, Not β-Sheet Structure
- De Novo α-Sheet Peptides Specifically Bind Toxic Oligomers
- α-Sheet Peptides Inhibit Aβ Aggregation and Cytotoxicity
- α-Sheet Designs Decrease Toxic Oligomers in AD Mouse Model
- α-Sheet Peptides Inhibit Aβ-Induced Paralysis in AD C. elegans Model
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