Rationally Designed Peptide-Based Inhibitor of Aβ42 Fibril Formation and Toxicity: A Potential Therapeutic Strategy for Alzheimer's Disease.
Files
(Published version)
Date
2020
Authors
Horsley, J.R.
Jovcevski, B.
Wegener, K.L.
Yu, J.
Pukala, T.L.
Abell, A.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Biochemical Journal, 2020; 477(11):2039-2054
Statement of Responsibility
John R. Horsley, Blagojce Jovcevski, Kate L. Wegener, Jingxian Yu, Tara L. Pukala, and Andrew D. Abell
Conference Name
Abstract
Amyloid beta peptide (Aβ42) aggregation in the brain is thought to be responsible for the onset of Alzheimer’s disease, an insidious condition without an effective treatment or cure. Hence, a strategy to prevent aggregation and subsequent toxicity is crucial. Bioinspired peptide-based molecules are ideal candidates for the inhibition of Aβ42 aggregation, and are currently deemed to be a promising option for drug design. In this study, a hexapeptide containing a self-recognition component unique to Aβ42 was designed to mimic the β-strand hydrophobic core region of the Aβ peptide. The peptide is comprised exclusively of D-amino acids to enhance specificity towards Aβ42, in conjunction with a C-terminal disruption element to block the recruitment of Aβ42 monomers on to fibrils. The peptide was rationally designed to exploit the synergy between the recognition and disruption components, and incorporates features such as hydrophobicity, β-sheet propensity, and charge, that all play a critical role in the aggregation process. Fluorescence assays, native ion-mobility mass spectrometry (IM-MS) and cell viability assays were used to demonstrate that the peptide interacts with Aβ42 monomers and oligomers with high specificity, leading to almost complete inhibition of fibril formation, with essentially no cytotoxic effects. These data define the peptide-based inhibitor as a potentially potent anti-amyloid drug candidate for this hitherto incurable disease.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2020 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).