Degradation of tau by lysosomal enzyme cathepsin D: Implication for Alzheimer neurofibrillary degeneration

Agnes Kenessey, Parimala Nacharaju, Li Wen Ko, Shu Hui Yen

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152 Scopus citations


The degradation of different isoforms of human recombinant tau (R-tau; T39, T40, and T44) and fetal tau (F-tau) by cathepsin D (CD) was investigated. Gel electrophoresis and Coomassie Blue staining of different R- tau species digested at pH 3.5 showed very little differences in CD susceptibility. Immunoblotting analyses revealed that amino and carboxy termini of tau were cleaved before other regions. F-tau was most vulnerable to proteolysis at both termini. Digestion of R-tau with 0.01 unit of CD/ml at pH 3.5 resulted in cleavage between Phe8-Glu9, Met419-Val420, Thr427-Leu426-Ala429, and Leu436-Ala437 as determined by amino acid sequencing and mass spectroscopy (numbering of amino acids was based on T40). With higher concentrations of CD (1 unit/ml), additional sites of digestion were detected between amine acids 34-161, 200-257, and 267-358. The cleavage sites at amine acids 34-161 and 267-358 were observed at pH 3.5, whereas that at amine acids 200-257 was detected at pH 7.0. Our results suggest that CD cleavage of tau could generate tau fragments with intact microtubule binding domains, which could have a role in the pathogenesis of paired helical filaments (PHFs) in Alzheimer's disease. Such proteolysis might also contribute to the changes of PHF phenotype observed in intracellular and extracellular tangles.

Original languageEnglish (US)
Pages (from-to)2026-2038
Number of pages13
JournalJournal of Neurochemistry
Issue number5
StatePublished - Nov 1997


  • Alzheimer's disease
  • Cathepsin D
  • Degradation sites
  • Tau

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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