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Tau Released from Paired Helical Filaments with Formic Acid or Guanidine Is Susceptible to Calpain‐Mediated Proteolysis
Author(s) -
Yang LiangSheng,
GordonKrajcer Wanda,
KsiezakReding Hanna
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69041548.x
Subject(s) - proteolysis , chemistry , glial fibrillary acidic protein , guanidine , calpain , biochemistry , formic acid , microbiology and biotechnology , tau protein , phosphorylation , biology , medicine , alzheimer's disease , immunohistochemistry , enzyme , immunology , disease
Paired helical filaments (PHFs), a characteristic neuropathologic finding in Alzheimer's disease brain, are abnormal fibrillary forms of hyperphosphorylated tau (PHF‐tau), which have been shown to be highly resistant to calpain digestion. Either excessive phosphorylation or fibrillary arrangement of tau proteins in PHFs may play a role in proteolytic resistance by limiting access to calpain recognition/digestion sites. To determine the contribution of the fibrillary conformation, isolated PHFs were subjected to treatment with either formic acid or guanidine. Both procedures effectively abolished the fibrillary structure of PHF but preserved PHF‐tau immunoreactivity using a panel of antibodies that recognize nonphosphorylated and phosphorylated epitopes. These treatments also significantly increased the sensitivity of PHF‐tau polypeptides to calpain proteolysis as shown by significant decreases in the half‐life ( t 1/2 ) from the infinite with native PHF to 44 min and 4.4 min in formic acid‐ or guanidine‐treated samples, respectively. In contrast, the sensitivity of normal fetal tau (3.4 min) was either decreased (5.9 min) or unaffected (3.6 min) by similar treatment. Our results indicate that after guanidine treatment, the sensitivity of PHF to calpain resembles that of fetal tau. These results strongly suggest that the fibrillary structure of PHF‐tau, rather than hyperphosphorylation, is the major factor responsible for the resistance of abnormal filaments to calpain‐mediated proteolysis.