Mechanisms of Transthyretin Inhibition of beta-Amyloid Aggregation In Vitro

作者：Li Xinyi^*; Zhang Xin; Ladiwala Ali Reza A; Du Deguo; Yadav Jay K; Tessier Peter M; Wright Peter E; Kelly Jeffery W; Buxbaum Joel N

来源：Journal of Neuroscience, 2013, 33(50): 19423-19433.

DOI：10.1523/JNEUROSCI.2561-13.2013

Tissue-specific overexpression of the human systemic amyloid precursor transthyretin (TTR) ameliorates Alzheimer%26apos;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 %26lt;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.

• 出版日期2013-12-11