TY - JOUR
T1 - Degradation of tau by lysosomal enzyme cathepsin D
T2 - Implication for Alzheimer neurofibrillary degeneration
AU - Kenessey, Agnes
AU - Nacharaju, Parimala
AU - Ko, Li Wen
AU - Yen, Shu Hui
PY - 1997/11
Y1 - 1997/11
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Cathepsin D
KW - Degradation sites
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=0030774852&partnerID=8YFLogxK
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U2 - 10.1046/j.1471-4159.1997.69052026.x
DO - 10.1046/j.1471-4159.1997.69052026.x
M3 - Article
C2 - 9349548
AN - SCOPUS:0030774852
SN - 0022-3042
VL - 69
SP - 2026
EP - 2038
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -