Conformational change as one of the earliest alterations of tau in Alzheimer's disease

Neurobiol Aging. Sep-Oct 2000;21(5):719-27. doi: 10.1016/s0197-4580(00)00157-3.

Abstract

Paired helical filaments (PHFs) found in Alzheimer's disease (AD) are mainly comprised of an abnormal form of tau (PHF-tau) that has undergone several post-translational modifications. Previous studies have shown that the monoclonal antibody MCI identifies a distinct conformation of tau in AD. We have assessed the temporal and spatial occurrence of the tau conformation recognized by MC1, and found its appearance in hippocampal neurons vulnerable to neurofibrillary tangle (NFT) formation in Braak Stage I and II cases. Electron microscopy has clearly demonstrated that this conformation precedes the formation of PHF. MC1 immunoaffinity chromatography also has identified a nonfilamentous, soluble pool of this abnormal tau. ELISA and immunoblotting have shown that this material is indistinguishable from that found in NFTs. This soluble component has the ability to self-assemble into PHFs in a concentration-dependent manner. Because the conformational change recognized by MCI appears before the assembly of and is found in PHF, but is not present in the normal brain, we suggest that the formation of the MCI epitope is one of the earliest pathological alterations of tau in AD.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Antibody Specificity
  • Blotting, Western
  • Hippocampus / chemistry*
  • Hippocampus / pathology
  • Humans
  • Microscopy, Electron
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Neurofibrillary Tangles / chemistry*
  • Neurofibrillary Tangles / pathology
  • Neurofibrillary Tangles / ultrastructure
  • Protein Conformation
  • Solubility
  • tau Proteins / analysis
  • tau Proteins / chemistry*
  • tau Proteins / immunology

Substances

  • tau Proteins