title: The N-methylated peptide SEN304 powerfully inhibits Aβ(1-42) toxicity by perturbing oligomer formation.
abstract: Oligomeric forms of β-amyloid (Aβ) have potent neurotoxic activity and are the primary cause of neuronal injury and cell death in Alzheimer's disease (AD). Compounds that perturb oligomer formation or structure may therefore be therapeutic for AD. We previously reported that d-[(chGly)-(Tyr)-(chGly)-(chGly)-(mLeu)]-NH(2) (SEN304) is able to inhibit Aβ aggregation and toxicity, shown primarily by thioflavin T fluorescence and MTT (Kokkoni, N. et al. (2006) N-Methylated peptide inhibitors of β-amyloid aggregation and toxicity. Optimisation of inhibitor structure. Biochemistry 45, 9906-9918). Here we extensively characterize how SEN304 affects Aβ(1-42) aggregation and toxicity, using biophysical assays (thioflavin T, circular dichroism, SDS-PAGE, size exclusion chromatography, surface plasmon resonance, traveling wave ion mobility mass spectrometry, electron microscopy, ELISA), toxicity assays in cell culture (MTT and lactate dehydrogenase in human SH-SHY5Y cells, mouse neuronal cell death and synaptophysin) and long-term potentiation in a rat hippocampal brain slice. These data, with dose response curves, show that SEN304 is a powerful inhibitor of Aβ(1-42) toxicity, particularly effective at preventing Aβ inhibition of long-term potentiation. It can bind directly to Aβ(1-42), delay β-sheet formation and promote aggregation of toxic oligomers into a nontoxic form, with a different morphology that cannot bind thioflavin T. SEN304 appears to work by inducing aggregation, and hence removal, of Aβ oligomers. It is therefore a promising lead compound for Alzheimer's disease.
authors.affiliation: Senexis Limited, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Hozefa
authors.initials: H
authors.lastname: Amijee
authors.forename: Clive
authors.initials: C
authors.lastname: Bate
authors.forename: Alun
authors.initials: A
authors.lastname: Williams
authors.forename: Jasmeet
authors.initials: J
authors.lastname: Virdee
authors.forename: Ross
authors.initials: R
authors.lastname: Jeggo
authors.forename: David
authors.initials: D
authors.lastname: Spanswick
authors.forename: David I C
authors.initials: DI
authors.lastname: Scopes
authors.forename: J Mark
authors.initials: JM
authors.lastname: Treherne
authors.forename: Sonia
authors.initials: S
authors.lastname: Mazzitelli
authors.forename: Ross
authors.initials: R
authors.lastname: Chawner
authors.forename: Claire E
authors.initials: CE
authors.lastname: Eyers
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Doig
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D052160:Benzothiazoles; D002470:Cell Survival; D002942:Circular Dichroism; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D051381:Rats; D020349:Surface Plasmon Resonance; D013844:Thiazoles; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D009842:Oligopeptides; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C577159:cyclohexylglycyl-tyrosyl-cyclohexylglycyl-cyclohexylglycyl-N-methylleucinamide; C009462:thioflavin T