Mechanisms of Transthyretin Inhibition of β-Amyloid Aggregation In Vitro

Tissue-specific overexpression of the human systemic amyloid precursor transthyretin (TTR) ameliorates Alzheimer's disease (AD) phenotypes in APP23 mice. TTR-beta-amyloid (A beta) complexes have been isolated from APP23 and some human AD brains. We now show that substoichiometric concentrations of TTR tetramers suppress A beta aggregation in vitro via an interaction between the thyroxine binding pocket of the TTR tetramer and A beta residues 18-21 (nuclear magnetic resonance and epitope mapping). The K-D is micromolar, and the stoichiometry is <1 for the interaction (isothermal titration calorimetry). Similar experiments show that engineered monomeric TTR, the best inhibitor of A beta fibril formation in vitro, did not bind A beta monomers in liquid phase, suggesting that inhibition of fibrillo-genesis is mediated by TTR tetramer binding to A beta monomer and both tetramer and monomer binding of A beta oligomers. The thousandfold greater concentration of tetramer relative to monomer in vivo makes it the likely suppressor of A beta aggregation and disease in the APP23 mice.