Earliest Stages of Tau Conformational Changes are Related to the Appearance of a Sequence of Specific Phospho-Dependent Tau Epitopes in Alzheimer's Disease1
Affiliations: [a] Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, México, D.F. México | [b] Department of Pathology, General Hospital of Mexico and Faculty of Medicine, UNAM, México | [c] Department of Physiology, Cell Biology CINVESTAV-IPN, México, D.F. México
Correspondence:
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Corresponding author: R. Mena, Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, México, D.F. México. C.P. 07360. Tel.: +52 55 50613800 ext 5130; E-mail: rmena@fisio.cinvestav.mx.
Note: [1] Financial support by CONACyT grants N° 47630 (RM) and 41023/A1 (FG-S).
Note: [2] Program BSC Metropolitan Autonomous University-Xochimilco.
Abstract: Neurofibrillary tangles (NFT) and dystrophic neurites represent dense cytoplasmic accumulations of abnormal polymers in the brain of patients with Alzheimer's disease (AD). These polymers are referred to as paired helical filaments (PHFs) whose main structural core is composed of tau protein. Tau processing has been associated with hyperphosphorylation and truncation that results in PHF assembly. Both molecular events appear to cause conformational change of tau molecules [11,17,32]. In this regard, in a previous work focused on the analysis of patterns of immunolabeling in pre-tangle cells, we found that regional changes precede the structural modifications in tau [32]. In the present study, we further analyzed the early stages of tau processing in pre-tangle cells by using a variety of immunological markers of specific N-terminus phosphorylation tau sites. We used AT100, TG-3, AT8, pT231, Alz-50, Tau-C3 and 423 antibodies that recognize different abnormal tau epitopes in AD brains. These antibodies were combined and analyzed using a confocal microscope. Our results indicate that the early stages of abnormal tau processing are characterized by a sequential appearance of specific phospho-dependent epitope. The cascade of appearance of the antibodies is: pT231 → TG-3 → AT8 → AT100 → Alz-50. In addition; truncation at Asp-421 of the C-terminus of tau protein, as detected by Tau-C3, is also an early molecular event in tau protein aggregation prior to PHF formation in AD.
