(544d) Transthyretin As Both Sensor and Scavenger of Toxic Abeta Oligomers

Transthyretin (TTR) is a homotetrameric transport protein, assembled from monomers that each contains two four-stranded beta-sheets and a short alpha-helix and loop. In the tetramer, the ‘inner’ beta-sheet forms a hydrophobic pocket while the helix and loop are solvent-exposed. Beta-amyloid (Abeta) aggregates bind to TTR, and the binding is significantly reduced in mutants L82A (on the loop) and L110A (on the inner beta-sheet). Wild-type TTR, but not L82A or L110A, protected against Abeta toxicity, providing a direct link between TTR-Abeta binding, and TTR-mediated cytoprotection. Protection is afforded at substoichiometric (1:100) TTR:Abeta molar ratios, and binding of Abeta to TTR is highest for partially aggregated materials and decreased for freshly-prepared or heavily aggregated Abeta, suggesting that TTR binds selectively to soluble toxic Abeta oligomers. A novel technique, nanoparticle tracking, is used to show that TTR arrests Abeta aggregation by both preventing formation of new aggregates and inhibiting growth of existing aggregates. TTR tetramers are normally quite stable. However, the quaternary structure of wild-type and L110A, but not L82A, was destabilized when co-incubated with Abeta, suggesting that Abeta binding to L82 triggers tetramer dissociation. Thus, partially folded (and aggregated) Abeta triggers partial unfolding of TTR. Interestingly, TTR monomers bind more Abeta than do tetramers, presumably because the hydrophobic ‘inner’ sheet is solvent-exposed upon tetramer disassembly. Therefore, partial loss of TTR quaternary structure is advantageous, by enhancing further binding of Abeta aggregates. Taken together, these results suggest a novel mechanism of action for TTR: the EF helix/loop ‘senses’ the presence of soluble toxic Abeta oligomers, triggering destabilization of TTR tetramers and exposure of the hydrophobic inner sheet, which then ‘scavenges’ these toxic oligomers and prevents them from causing cell death.