title: Mechanisms of transthyretin inhibition of β-amyloid aggregation in vitro.
abstract: Tissue-specific overexpression of the human systemic amyloid precursor transthyretin (TTR) ameliorates Alzheimer's disease (AD) phenotypes in APP23 mice. TTR-β-amyloid (Aβ) complexes have been isolated from APP23 and some human AD brains. We now show that substoichiometric concentrations of TTR tetramers suppress Aβ aggregation in vitro via an interaction between the thyroxine binding pocket of the TTR tetramer and Aβ 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 Aβ fibril formation in vitro, did not bind Aβ monomers in liquid phase, suggesting that inhibition of fibrillogenesis is mediated by TTR tetramer binding to Aβ monomer and both tetramer and monomer binding of Aβ oligomers. The thousand-fold greater concentration of tetramer relative to monomer in vivo makes it the likely suppressor of Aβ aggregation and disease in the APP23 mice.
authors: Departments of Molecular and Experimental Medicine, Chemistry, and Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180, Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, and Max Planck Research Unit for Enzymology of Protein Folding and Martin Luther University, D-06120 Halle, Germany.
authors: Xinyi
authors: X
authors: Li
authors: Xin
authors: X
authors: Zhang
authors: Ali Reza A
authors: AR
authors: Ladiwala
authors: Deguo
authors: D
authors: Du
authors: Jay K
authors: JK
authors: Yadav
authors: Peter M
authors: PM
authors: Tessier
authors: Peter E
authors: PE
authors: Wright
authors: Jeffery W
authors: JW
authors: Kelly
authors: Joel N
authors: JN
authors: Buxbaum
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000939:Epitopes; D051379:Mice; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000939:Epitopes; D011228:Prealbumin