title: Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer's disease.
abstract: Phosphorylation, cleavage and conformational changes in tau protein all play pivotal roles during Alzheimer's disease (AD). In an effort to determine the chronological sequence of these changes, in this study, using confocal microscopy, we compared phosphorylation at several sites (Ser(199/202/396/404/422)-Thr(205) and the second repeat domain), cleavage of tau (D(421)) and the canonical conformational Alz-50 epitope. While all of these posttranslational modifications are found in neurofibrillary tangles (NFTs) at all stages of the disease, we found significantly higher numbers of phospho-tau positive NFTs when compared with cleaved tau (P = 0.006 in Braak III; P = 0.002 in Braak IV; P = 0.012 in Braak V) or compared with the Alz-50 epitope (P < 0.05). Consistent with these findings, in a double transgenic mice model (Tet/GSK-3beta/VLW) overexpressing the enzyme glycogen synthase kinase-3beta (GSK-3beta) and tau with a triple FTDP-17 mutation (VLW) with AD-like neurodegeneration, phosphorylation at sites Ser(199/202)-Thr(205) was greater than truncated tau. Taken together, these data strongly support the notion that the conformational changes and truncation of tau occur after the phosphorylation of tau. We propose two probable pathways for the pathological processing of tau protein during AD, either phosphorylation and cleavage of tau followed by the Alz-50 conformational change or phosphorylation followed by the conformational change and cleavage as the last step.
authors.affiliation: Department of Cell Biology, CINVESTAV-IPN, México City, México.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mondragón-Rodríguez
authors.forename: Gustavo
authors.initials: G
authors.lastname: Basurto-Islas
authors.forename: Ismael
authors.initials: I
authors.lastname: Santa-Maria
authors.forename: Raúl
authors.initials: R
authors.lastname: Mena
authors.forename: Lester I
authors.initials: LI
authors.lastname: Binder
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Francisco
authors.initials: F
authors.lastname: García-Sierra
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D012720:Severity of Illness Index; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins