Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease

Peleg M. Horowitz, Kristina R. Patterson, Angela L. Guillozet-Bongaarts, Matthew R. Reynolds, Christopher A. Carroll, Susan T. Weintraub, David A. Bennett, Vincent L. Cryns, Robert W. Berry, Lester I. Binder

Research output: Contribution to journalArticle

172 Scopus citations

Abstract

Alzheimer's disease (AD) is a progressive amnestic dementia that involves post-translational hyperphosphorylation, enzymatic cleavage, and conformational alterations of the microtubule-associated protein tau. The truncation state of tau influences many of its pathologic characteristics, including its ability to assume AD-related conformations and to assemble into filaments. Cleavage also appears to be an important marker in AD progression. Although C-terminal truncation of tau at D421 has recently been attributed to the apoptotic enzyme caspase-3, N-terminal processing of the protein remains mostly uncharacterized. Here, we report immunohistochemical staining in a cohort of 35 cases ranging from noncognitively impaired to early AD with a panel of three N-terminal anti-tau antibodies: Tau-12, 5A6, and 9G3-pY18. Of these three, the phosphorylation-independent epitope of 5A6 was the earliest to emerge in the pathological lesions of tau, followed by the appearance of the Tau-12 epitope. The unmasking of the Tau-12 epitope in more mature 5A6-positive tangles was not correlated with tau phosphorylation at tyrosine 18 (9G3-pY18). Still, later in the course of tangle evolution, the extreme N terminus of tau was lost, correlating temporally with the appearance of a C-terminal caspase-truncated epitope lacking residues 422-441. In addition, caspase-6 cleaved the N terminus of tau in vitro, preventing immunoreactivity with both Tau-12 and 5A6. Mass spectrometry confirmed that the in vitro caspase-6 truncation site is D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. Collectively, these results suggest a role for caspase-6 and N-terminal truncation of tau during neurofibrillary tangle evolution and the progression of Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)7895-7902
Number of pages8
JournalJournal of Neuroscience
Volume24
Issue number36
DOIs
StatePublished - Sep 8 2004

Keywords

  • Alzheimer's disease
  • Caspase
  • Neurofibrillary tangle
  • Tau
  • Truncation
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)

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