Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease

Angela L. Guillozet-Bongaarts*, Francisco Garcia-Sierra, Matthew R. Reynolds, Peleg M. Horowitz, Yifan Fu, Tianyi Wang, Michael E. Cahill, Eileen H. Bigio, Robert W. Berry, Lester I. Binder

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

172 Scopus citations

Abstract

The microtubule-associated protein, tau, is a highly soluble molecule that is nonetheless capable of self-association into filamentous deposits characteristic of a number of neurodegenerative diseases. This state change is thought to be driven by phosphorylation and/or C-terminal truncation events resulting in intracellular inclusions, such as the neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Previously, we reported the existence of a novel truncation event, cleavage at aspartic acid421, presumably by a caspase, and also described a monoclonal antibody (Tau-C3) specific for tau cleaved at this site. Here, we report the timing of this cleavage event relative to other antibody-targeted alterations in the tau molecule during the course of NFT evolution in AD. Immunohistochemical studies indicate that cleavage at aspartic acid421 occurs after formation of the Alz50 epitope but prior to formation of the Tau-66 epitope and truncation at glutamic acid 391 (formation of the MN423 epitope). Thus, creation of the Tau-C3 epitope appears to occur relatively early in the disease state, contemporaneous with the initial Alz50 folding event that heralds the appearance of filamentous tau in NFTs, neuropil threads, and the dystrophic neurites surrounding amyloid plaques.

Original languageEnglish (US)
Pages (from-to)1015-1022
Number of pages8
JournalNeurobiology of Aging
Volume26
Issue number7
DOIs
StatePublished - Jul 2005

Keywords

  • Caspase
  • Cleavage
  • Conformation
  • Tangle formation
  • Tau-C3

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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