Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is a progressive amnestic dementia that involves post-translational hyperphosphorylation, enzymatic cleavage, and conformational alterations of the microtubule-associated protein tau. The truncation state of tau influences many of its pathologic characteristics, including its ability to assume AD-related conformations and to assemble into filaments. Cleavage also appears to be an important marker in AD progression. Although C-terminal truncation of tau at D421 has recently been attributed to the apoptotic enzyme caspase-3, N-terminal processing of the protein remains mostly uncharacterized. Here, we report immunohistochemical staining in a cohort of 35 cases ranging from noncognitively impaired to early AD with a panel of three N-terminal anti-tau antibodies: Tau-12, 5A6, and 9G3-pY18. Of these three, the phosphorylation-independent epitope of 5A6 was the earliest to emerge in the pathological lesions of tau, followed by the appearance of the Tau-12 epitope. The unmasking of the Tau-12 epitope in more mature 5A6-positive tangles was not correlated with tau phosphorylation at tyrosine 18 (9G3-pY18). Still, later in the course of tangle evolution, the extreme N terminus of tau was lost, correlating temporally with the appearance of a C-terminal caspase-truncated epitope lacking residues 422-441. In addition, caspase-6 cleaved the N terminus of tau in vitro, preventing immunoreactivity with both Tau-12 and 5A6. Mass spectrometry confirmed that the in vitro caspase-6 truncation site is D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. Collectively, these results suggest a role for caspase-6 and N-terminal truncation of tau during neurofibrillary tangle evolution and the progression of Alzheimer's disease.

• Authors: Peleg M Horowitz, Kristina R Patterson, Angela L Guillozet-Bongaarts, Matthew R Reynolds, Christopher A Carroll, Susan T Weintraub, David A Bennett, Vincent L Cryns, Robert W Berry, Lester I Binder
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 24 Issue 36 Pg. 7895-902 (Sep 08 2004) ISSN: 1529-2401 [Electronic] United States
• PMID: 15356202 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Epitopes
• Nerve Tissue Proteins
• Proto-Oncogene Proteins
• Recombinant Proteins
• tau Proteins
• FYN protein, human
• Proto-Oncogene Proteins c-fyn
• src-Family Kinases
• CASP6 protein, human
• Caspase 6
• Caspases

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (metabolism, pathology)
• Amino Acid Substitution
• Antibodies, Monoclonal (immunology)
• Antibody Specificity
• Apoptosis
• Caspase 6
• Caspases (physiology)
• Cohort Studies
• Disease Progression
• Epitopes (immunology)
• Female
• Humans
• Male
• Microscopy, Fluorescence
• Nerve Tissue Proteins (physiology)
• Neurofibrillary Tangles (chemistry)
• Neurons (metabolism, pathology)
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-fyn
• Recombinant Proteins (metabolism)
• Single-Blind Method
• Temporal Lobe (chemistry, pathology)
• src-Family Kinases (metabolism)
• tau Proteins (chemistry, immunology, metabolism)