Abstract 2390 Peptide-based Inhibitors of Amyloid Beta Oligomerization and Toxicity

Neurotoxic aggregates of amyloid beta (Aβ) peptide contribute to the etiology of Alzheimer's disease (AD). Aβ1-42 forms oligomeric structures that undergo further aggregation into protofibrils and fibrils. Oligomeric Aβ1-42 is more toxic than monomers or mature fibrils. Studies on suppression of Aβ cytotoxicity by peptides, including those derived by Aβ, have been conducted before, but peptides encompassing the whole Aβ sequence have not been systematically analyzed. In this work, seven distinct but overlapping Aβ fragments were used to identify their individual aggregation propensities and to assess their effects on Aβ1-42 oligomerization and cytotoxicity. Aβ1-42 was allowed to aggregate and form oligomeric assemblies in aqueous buffer for 4 h in the absence or presence of 2-fold molar excess of an Aβ fragment. MTS cytotoxicity analysis on PC12 cell culture then recorded the impact of each fragment on Aβ1-42 cytotoxicity as well as the toxicity of the fragments themselves. An enzyme-linked immunosorbent assay that detects oligomeric Aβ was used to determine the effect of each fragment on Aβ1-42 oligomerization after 4 h of aggregation. Four fragments of Aβ1-42 inhibited the toxicity of oligomeric Aβ1-42 to various degrees, while two others conferred no cellular protection against Aβ1-42 toxicity. Interestingly, one fragment enhanced Aβ1-42 toxicity after 4 h of aggregation. Three of the four fragments that blocked Aβ1-42 toxicity disrupted oligomer formation at different levels, showing correlation between the inhibition of Aβ1-42 aggregation and the inhibition of cellular toxicity. This result suggests that fragment intercalation into the growing Aβ aggregates may disrupt the oligomerization process and thereby mitigate the peptide's toxicity. Fragments that block both Aβ1-42 aggregation and toxicity represent potential targets for therapeutic development for AD. This project is funded by the Florida Department of Health, Award #21A06 to Dr. Suren Tatulian. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Florida Department of Health.