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

Qin Cao, Daniel H. Anderson, Wilson Y. Liang, Joshua Chou, Lorena Saelices

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The protective effect of transthyretin (TTR) on cellular toxicity of b-amyloid (Ab) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, the pathogenic aggregation of which causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Ab, a protein associated with Alzheimer's disease. TTR binds Ab, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we investigate whether the amyloidogenic ability of TTR and its antiamyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Ab oligomers. These findings suggest that the Ab-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 Ab aggregation and toxicity, mimicking TTR cellular protection. EM, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Ab oligomer formation and also promotes the formation of nontoxic, nonamyloid amorphous aggregates, which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Ab catalyzed by Ab fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)14015-14024
Number of pages10
JournalJournal of Biological Chemistry
Volume295
Issue number41
DOIs
StatePublished - Oct 9 2020
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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