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Mechanisms of transthyretin inhibition of beta-amyloid aggregation in vitro

Academic Article
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Overview

authors

  • Li, X.
  • Zhang, X.
  • Ladiwala, A. R. A.
  • Du, D.
  • Yadav, J. K.
  • Tessier, P. M.
  • Wright, Peter
  • Kelly, Jeffery
  • Buxbaum, Joel

publication date

  • December 2013

journal

  • Journal of Neuroscience  Journal

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.

subject areas

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Animals
  • Brain
  • Epitopes
  • Mice
  • Prealbumin
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Identity

PubMed Central ID

  • PMC3858619

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.2561-13.2013

PubMed ID

  • 24336709
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Additional Document Info

start page

  • 19423

end page

  • 19433

volume

  • 33

issue

  • 50

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