Degradation of Tau by Lysosomal Enzyme Cathepsin D: Implication for Alzheimer Neurofibrillary Degeneration

• Published in: Journal of neurochemistry Vol. 69; no. 5; pp. 2026 - 2038
• Main Authors: Kenessey, Agnes, Nacharaju, Parimala, Ko, Li‐wen, Yen, Shu‐Hui
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.11.1997; Blackwell
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amino Acid Sequence; Animals; Biological and medical sciences; Cathepsin D; Cathepsin D - metabolism; Cattle; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Degradation sites; Fetus; Humans; Hydrogen-Ion Concentration; Hydrolysis; Lysosomes - enzymology; Mass Spectrometry; Medical sciences; Molecular Sequence Data; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurofibrils - metabolism; Neurofibrils - pathology; Neurology; Peptide Fragments - chemistry; Peptide Fragments - isolation & purification; Phosphorylation; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Spleen - enzymology; Tau; tau Proteins - chemistry; tau Proteins - metabolism; Nervous system diseases; Molecular form; 4-α-Glucanotransferase; Enzyme; Alzheimer disease; Pathogenesis; Transferases; Glycosyltransferases; In vitro; Cerebral disorder; Peptidases; Tau protein; Central nervous system disease; Hydrolases; Aspartic endopeptidases; Hexosyltransferases; Degenerative disease; Cathepsin D; Degeneration; Aminoacid sequence
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.1997.69052026.x

: 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‐Leu428‐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 amino acids 34–161, 200–257, and 267–358. The cleavage sites at amino acids 34–161 and 267–358 were observed at pH 3.5, whereas that at amino 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.