The N-methylated peptide SEN304 powerfully inhibits Aβ(1-42) toxicity by perturbing oligomer formation.

Oligomeric forms of beta-amyloid (A beta) 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)]-NH2 (SEN304) is able to inhibit A beta aggregation and toxicity, shown primarily by thioflavin T fluorescence and MTT (Kokkoni, N. et al. (2006) N-Methylated peptide inhibitors of beta-amyloid aggregation and toxicity. Optimisation of inhibitor structure. Biochemistry 45, 9906-9918). Here we extensively characterize how SEN304 affects A beta(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 A beta(1-42) toxicity, particularly effective at preventing A beta inhibition of long-term potentiation. It can bind directly to A beta(1-42), delay beta-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 A beta oligomers. It is therefore a promising lead compound for Alzheimer's disease.