Proapoptotic effects of tau cleavage product generated by caspase-3

Neurobiol Dis. 2001 Feb;8(1):162-72. doi: 10.1006/nbdi.2000.0335.


Using an in vitro translation assay to screen a human brain cDNA library, we isolated the microtubule-associated protein Tau and determined it to be a caspase-3 substrate whose C-terminal cleavage occurred during neuronal apoptosis. DeltaTau, the 50-kDa cleavage product, was detected by Western blot in apoptotic cortical cells probed with anti-PHF-1 and anti-Tau-5 antibodies, but not anti-T-46 antibody which recognizes the C-terminus. Overexpression of DeltaTau in SK-N-BE2(C) cells significantly increased the incidence of cell death. Staurosporine-induced Tau cleavage was blocked by 20 microM z-Asp-Glu-Val-Asp-chloromethylketone, a caspase-3 inhibitor, and in vitro, Tau was selectively cleaved by caspase-3 or calpain, a calcium-activated protease, but not by caspases-1, -8, or -9. (D421E)-Tau, a mutant in which Asp421 was replaced with a Glu, was resistant to cleavage by caspase-3 and tended to suppress staurosporine-induced cell death more efficiently than did wild-type Tau in both transient and stable expression systems. Finally, the incidence of DeltaTau-induced cell death was augmented by expression of Abeta precursor protein (APP) or Swedish APP mutant. Taken together, these results suggest that the caspase-3 cleavage product of Tau may contribute to the progression of neuronal cell death in Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / pharmacology
  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Line
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Indicators and Reagents
  • Peptide Fragments / genetics
  • Peptide Fragments / toxicity
  • Plasmids / genetics
  • Recombinant Proteins / pharmacology
  • Transfection
  • beta-Galactosidase / biosynthesis
  • tau Proteins / genetics
  • tau Proteins / metabolism*
  • tau Proteins / toxicity*


  • Amyloid beta-Protein Precursor
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Indicators and Reagents
  • Peptide Fragments
  • Recombinant Proteins
  • tau Proteins
  • beta-Galactosidase
  • CASP3 protein, human
  • Caspase 3
  • Caspases