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Decreasing amyloid toxicity through an increased rate of aggregation.

ABSTRACT: Amyloid ? is one of the peptides involved in the onset of Alzheimer's disease, yet the structure of the toxic species and its underlying mechanism remain elusive on account of the dynamic nature of the A? oligomerisation process. While it has been reported that incubation of Amyloid ? (1-42) sequences (A?42) lead to formation of aggregates that vary in morphology and toxicity, we demonstrate that addition of a discrete macrocyclic host molecule, cucurbit[8]uril (CB[8]), substantially reduces toxicity in the neuronal cell line SH-SY5Y. The macrocycle preferentially targets Phe residues in A?42 complexing them in a 2?:?1 fashion in neighboring peptide strands. A small but significant structural 'switch' occurs, which induces an increased aggregation rate, suggesting a different cell-uptake mechanism for A?42 in the presence of CB[8]. Dramatically increasing the rate of A?42 aggregation with CB[8] bypasses the toxic, oligomeric state offering an alternative approach to counter Alzheimer's disease.

SUBMITTER: Sonzini S

PROVIDER: S-EPMC5310522 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Decreasing amyloid toxicity through an increased rate of aggregation.

Sonzini Silvia S Stanyon Helen F HF Scherman Oren A OA

Physical chemistry chemical physics : PCCP 20170101 2

Amyloid β is one of the peptides involved in the onset of Alzheimer's disease, yet the structure of the toxic species and its underlying mechanism remain elusive on account of the dynamic nature of the Aβ oligomerisation process. While it has been reported that incubation of Amyloid β (1-42) sequences (Aβ42) lead to formation of aggregates that vary in morphology and toxicity, we demonstrate that addition of a discrete macrocyclic host molecule, cucurbit[8]uril (CB[8]), substantially reduces tox ...[more]

PMID: 27982149

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