Intracellular selection of peptide inhibitors that target disulphide-bridged Aβ42 oligomers

Nicola Acerra, Neil. M. Kad, Harish Cheruvara, Jody M. Mason

Research output: Contribution to journalArticlepeer-review

9 Citations (SciVal)
191 Downloads (Pure)

Abstract

The β-amyloid (Aβ) peptide aggregates into a number of soluble and insoluble forms, with soluble oligomers thought to be the primary factor implicated in Alzheimer's disease pathology. As a result, a wide range of potential aggregation inhibitors have been developed. However, in addition to problems with solubility and protease susceptibility, many have inadvertently raised the concentration of these soluble neurotoxic species. Sandberg et al. previously reported a β-hairpin stabilized variant of Aβ42 that results from an intramolecular disulphide bridge (A21C/A31C; Aβ42cc), which generates highly toxic oligomeric species incapable of converting into mature fibrils. Using an intracellular protein-fragment complementation (PCA) approach, we have screened peptide libraries using E. coli that harbor an oxidizing environment to permit cytoplasmic disulphide bond formation. Peptides designed to target either the first or second β-strand have been demonstrated to bind to Aβ42cc, lower amyloid cytotoxicity, and confer bacterial cell survival. Peptides have consequently been tested using wild-type Aβ42 via ThT binding assays, circular dichroism, MTT cytotoxicity assays, fluorescence microscopy, and atomic force microscopy. Results demonstrate that amyloid-PCA selected peptides function by both removing amyloid oligomers as well as inhibiting their formation. These data further support the use of semirational design combined with intracellular PCA methodology to develop Aβ antagonists as candidates for modification into drugs capable of slowing or even preventing the onset of AD.
Original languageEnglish
Pages (from-to)1262-1274
Number of pages13
JournalProtein Science
Volume23
Issue number9
Early online date2 Jul 2014
DOIs
Publication statusPublished - Sept 2014

Fingerprint

Dive into the research topics of 'Intracellular selection of peptide inhibitors that target disulphide-bridged Aβ42 oligomers'. Together they form a unique fingerprint.

Cite this