Interaction of transthyretin with amyloid beta-protein: binding and inhibition of amyloid formation

Ciba Found Symp. 1996;199:146-60; discussion 160-4. doi: 10.1002/9780470514924.ch10.

Abstract

Aggregated amyloid beta-protein (A beta) is a key component of the amyloid depositions found in the brains of patients with Alzheimer's disease. In contrast, in cerebrospinal fluid (CSF), A beta is found in a soluble form. The analysis of complexes of A beta with CSF proteins in a KBr gradient revealed an association of A beta only with free proteins and not with lipoprotein particles. Transthyretin (TTR), a second major CSF protein, formed SDS-stable complexes with A beta and significantly decreased the rate of A beta fibril formation. In physiological buffers and CSF, TTR exclusively decreased the level of A beta pentamers. Endogenous TTR-A beta complexes were detected in human CSF by immunoprecipitation. Using site-directed mutagenesis and computer-assisted modelling, we identified amino acid residues on the surface of the TTR monomer that interact with A beta. Specific TTR immunoreactivity was detected in multiple cortical neurons and astrocytes in the human brain. We propose that A beta binding proteins play a key role in the modulation of A beta aggregation and normally prevent amyloid formation in biological fluids and in the brain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism*
  • Amyloid / antagonists & inhibitors
  • Amyloid / biosynthesis
  • Amyloid / cerebrospinal fluid
  • Amyloid / chemistry
  • Amyloid / metabolism
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Amyloidosis / etiology
  • Amyloidosis / metabolism
  • Brain / metabolism*
  • Brain / ultrastructure
  • Humans
  • Immunohistochemistry
  • Microscopy, Electron
  • Prealbumin / cerebrospinal fluid
  • Prealbumin / chemistry
  • Prealbumin / metabolism*
  • Precipitin Tests
  • Protein Binding

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Prealbumin
  • transthyretin-related amyloid fibril protein, human