title: Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in Alzheimer's disease.
abstract: Neurofibrillary tangles (NFTs) are the neuropathological hallmarks in Alzheimer's disease (AD). Densities of NFTs correlate with the dementia status. NFTs reflect the intracellular accumulation of abnormal paired helical filaments (PHFs) composed of the microtubule-associated protein tau. Hyperphosphorylation and truncation have been proposed as key events leading to the genesis of PHFs. A recent hypothesis involving conformational changes has been emerging. These structural modifications of the tau protein were detected by monoclonal antibodies (mAbs) recognizing discontinuous epitopes along the tau molecule such as Alz-50, Tau-66 and MC1. A new mAb, TG-3, detects an early pathology in AD. The epitope of mAb TG-3 maps to phosphorylated Thr231 when the tau molecule is conformationally altered. In the present study, we used confocal microscopy to analyze the state of tau molecule adopting the TG-3 conformation during tangle formation. We also compared mAb TG-3 immunoreactivity with that of mAb Alz-50. Immunoelectronmicroscopy was also performed. N- and C- termini markers evidenced that the tau molecule is intact when it adopts the TG-3 conformation. In addition to NFT, mAb TG-3 also recognized NFT-not bearing-neurons suggesting an early processing of tau prior to NFT formation. Ultrastructural analysis evidenced the presence of TG-3 and Alz-50 immunoreactive products on organelles including mitochondria and endoplasmic reticulum. Nuclear heterochromatin was densely immunolabelled. These results together with the fact that TG-3 immunoreactivity is related to intact tau suggest that the conformation recognized by TG-3 is early staged in the neuronal pathology of AD. In addition, we document that the earliest changes in tau occur closely associated with organelles and heterochromatin.
authors.affiliation: Department of Physiology, Biophysics and Neurociences, CINVESTAV-IPN, México, DF México.
authors.forename: José
authors.initials: J
authors.lastname: Luna-Muñoz
authors.forename: Francisco
authors.initials: F
authors.lastname: García-Sierra
authors.forename: Viviana
authors.initials: V
authors.lastname: Falcón
authors.forename: Ivón
authors.initials: I
authors.lastname: Menéndez
authors.forename: Laura
authors.initials: L
authors.lastname: Chávez-Macías
authors.forename: Raúl
authors.initials: R
authors.lastname: Mena
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D000941:Antigens / Q000276:immunology*; D003599:Cytoskeleton / Q000473:pathology*; D018728:Entorhinal Cortex / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D010766:Phosphorylation; D011487:Protein Conformation; D016875:tau Proteins
chemical_list: C056167:Alzheimer's disease antigen; D000911:Antibodies, Monoclonal; D000941:Antigens; C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D016875:tau Proteins