title: 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.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. p-horowitz@md.northwestern.edu
authors.forename: Peleg M
authors.initials: PM
authors.lastname: Horowitz
authors.forename: Kristina R
authors.initials: KR
authors.lastname: Patterson
authors.forename: Angela L
authors.initials: AL
authors.lastname: Guillozet-Bongaarts
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reynolds
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Carroll
authors.forename: Susan T
authors.initials: ST
authors.lastname: Weintraub
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
authors.forename: Robert W
authors.initials: RW
authors.lastname: Berry
authors.forename: Lester I
authors.initials: LI
authors.lastname: Binder
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D017209:Apoptosis; D053178:Caspase 6; D020169:Caspases / Q000502:physiology*; D015331:Cohort Studies; D018450:Disease Progression; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000502:physiology*; D016874:Neurofibrillary Tangles / Q000737:chemistry*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D011994:Recombinant Proteins / Q000378:metabolism; D016037:Single-Blind Method; D013702:Temporal Lobe / Q000737:chemistry / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D016875:tau Proteins; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases; C505514:CASP6 protein, human; D053178:Caspase 6; D020169:Caspases