Proteolytic cleavage of polymeric tau protein by caspase-3: implications for Alzheimer disease.
Truncated tau protein at Asp(421) is associated with neurofibrillary pathology in Alzheimer disease (AD); however, little is known about its presence in the form of nonfibrillary aggregates. Here, we report immunohistochemical staining of the Tau-C3 antibody, which recognizes Asp(421)-truncated tau, in a group of AD cases with different extents of cognitive impairment. In the hippocampus, we found distinct nonfibrillary aggregates of Asp(421)-truncated tau. Unlike Asp(421)-composed neurofibrillary tangles, however, these nonfibrillary pathologies did not increase significantly with respect to the Braak staging and, therefore, make no significant contribution to cognitive impairment. On the other hand, despite in vitro evidence that caspase-3 cleaves monomeric tau at Asp(421), to date, this truncation has not been demonstrated to be executed by this protease in polymeric tau entities. We determined that Asp(421) truncation can be produced by caspase-3 in oligomeric and multimeric complexes of recombinant full-length tau in isolated native tau filaments in vitro and in situ in neurofibrillary tangles analyzed in fresh brain slices from AD cases. Our data suggest that generation of this pathologic Asp(421) truncation of tau in long-lasting fibrillary structures may produce further permanent toxicity for neurons in the brains of patients with AD.
From the Department of Cell Biology, Center of Research and Advanced Studies of the National Polytechnic Institute (JJJ-B, FG-S); Brain Bank LANSE, Center of Research and Advanced Studies of the National Polytechnic Institute (JL-M); and Department of Neuroscience, Center of Research and Advanced Studies of the National Polytechnic Institute (RM), Mexico City, México; Laboratory of Biochemistry and Brain Pathophysiology and AD Center, Prague Psychiatric Center, Prague, Czech Republic (ZK, DR); College of Sciences, University of Texas at San Antonio, San Antonio, Texas (GP); and Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, Michigan (LIB).
Jose J
JJ
Jarero-Basulto
Jose
J
Luna-Muñoz
Raul
R
Mena
Zdena
Z
Kristofikova
Daniela
D
Ripova
George
G
Perry
Lester I
LI
Binder
Francisco
F
Garcia-Sierra
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D001224:Aspartic Acid / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D053148:Caspase 3 / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008970:Molecular Weight; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009454:Neurofibrils / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure
D000590:Amino Acid Chloromethyl Ketones; D018696:Neuroprotective Agents; D009842:Oligopeptides; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D016875:tau Proteins; D001224:Aspartic Acid; D053148:Caspase 3