Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease.
The microtubule-associated protein, tau, is a highly soluble molecule that is nonetheless capable of self-association into filamentous deposits characteristic of a number of neurodegenerative diseases. This state change is thought to be driven by phosphorylation and/or C-terminal truncation events resulting in intracellular inclusions, such as the neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Previously, we reported the existence of a novel truncation event, cleavage at aspartic acid(421), presumably by a caspase, and also described a monoclonal antibody (Tau-C3) specific for tau cleaved at this site. Here, we report the timing of this cleavage event relative to other antibody-targeted alterations in the tau molecule during the course of NFT evolution in AD. Immunohistochemical studies indicate that cleavage at aspartic acid(421) occurs after formation of the Alz50 epitope but prior to formation of the Tau-66 epitope and truncation at glutamic acid(391) (formation of the MN423 epitope). Thus, creation of the Tau-C3 epitope appears to occur relatively early in the disease state, contemporaneous with the initial Alz50 folding event that heralds the appearance of filamentous tau in NFTs, neuropil threads, and the dystrophic neurites surrounding amyloid plaques.
Guillozet-Bongaarts
Angela L
AL
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA. LGD450@northwestern.edu
Garcia-Sierra
Francisco
F
Reynolds
Matthew R
MR
Horowitz
Peleg M
PM
Fu
Yifan
Y
Wang
Tianyi
T
Cahill
Michael E
ME
Bigio
Eileen H
EH
Berry
Robert W
RW
Binder
Lester I
LI
D000544:Alzheimer Disease / Q000378:metabolism*; D000941:Antigens / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique / Q000379:methods; D017353:Gene Deletion; D006801:Humans; D008954:Models, Biological; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011180:Postmortem Changes; D011499:Protein Processing, Post-Translational; D016875:tau Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
C056167:Alzheimer's disease antigen; D000941:Antigens; C430266:Tau-66; D016875:tau Proteins; D001224:Aspartic Acid