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

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

SUBMITTER: Shea D 

PROVIDER: S-EPMC6500163 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature