Proteolytic cleavage of polymeric tau protein by caspase-3: Implications for Alzheimer disease

Abstract

Truncated tau protein at Asp421 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 Asp421-truncated tau. Unlike Asp421-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 Asp421, to date, this truncation has not been demonstrated to be executed by this protease in polymeric tau entities. We determined that Asp421 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 Asp421 truncation of tau in long-lasting fibrillary structures may produce further permanent toxicity for neurons in the brains of patients with AD. Copyright © 2013 by the American Association of Neuropathologists, Inc.