The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin

Abstract

The protective effect of transthyretin (TTR) on cellular toxicity of amyloid-beta (A{beta}) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, whose pathogenic aggregation causes systemic amyloidosis. In contrast, many reports have shown that TTR binds amyloid-beta (A{beta}), associated with Alzheimers disease, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we question whether TTR amyloidogenic ability and its anti-amyloid inhibitory effect are associated. Our results indicate that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from A{beta} oligomers. These findings suggest that the A{beta} binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering A{beta} aggregation and toxicity, mimicking TTR cellular protection. This segment inhibits A{beta} oligomer formation and also promotes the formation of non-toxic, non-amyloid, amorphous aggregates which are more sensitive to protease digestion. This segment also inhibits seeding of A{beta} catalyzed by A{beta} fibrils extracted from the brain of an Alzheimers patient. Our results suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimers disease. Significance statementThe pathological landmarks of Alzheimers disease are the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques contain fibrous structures made of aggregated amyloid-beta (A{beta}). In 1982, Shirahama and colleagues observed the presence of transthyretin (TTR) in these plaques. TTR is a tetrameric protein whose aggregation causes transthyretin amyloidosis. However, TTR protects A{beta} from aggregating and causing toxicity to neurons. In this study, we show that the dissociation of TTR tetramers is required to inhibit cellular toxicity caused by A{beta}. In addition, we identified a minimum segment of TTR that inhibits A{beta} aggregation and cellular toxicity by the formation of amorphous aggregates that are sensitive to proteases, similar to the natural effect of TTR found by others in vivo.