Tau-66: evidence for a novel tau conformation in Alzheimer's disease

Ghoshal, N, F Garcia-Sierra, Y Fu, L A Beckett, E J Mufson, J Kuret, R W Berry and L I Binder

J Neurochem. 2001. 77(5):1372-85.

We have characterized a novel monoclonal antibody, Tau-66, raised against recombinant human tau. Immunohistochemistry using Tau-66 reveals a somatic-neuronal stain in the superior temporal gyrus (STG) that is more intense in Alzheimer's disease (AD) brain than in normal brain. In hippocampus, Tau-66 yields a pattern similar to STG, except that neurofibrillary lesions are preferentially stained if present. In mild AD cases, Tau-66 stains plaques lacking obvious dystrophic neurites (termed herein 'diffuse reticulated plaques') in STG and the hippocampus. Enzyme-linked immunosorbent assay (ELISA) analysis reveals that Tau-66 is specific for tau, as there is no cross-reactivity with MAP2, tubulin, Abeta(1-40), or Abeta(1-42), although Tau-66 fails to react with tau or any other polypeptide on western blots. The epitope of Tau-66, as assessed by ELISA testing of tau deletion mutants, appears discontinuous, requiring residues 155-244 and 305-314. Tau-66 reactivity exhibits buffer and temperature sensitivity in an ELISA format and is readily abolished by SDS treatment. Taken together these lines of evidence indicate that the Tau-66 epitope is conformation-dependent, perhaps involving a close interaction of the proline-rich and the third microtubule-binding regions. This is the first indication that tau can undergo this novel folding event and that this conformation of tau is involved in AD pathology.

Keywords: Aged, Aged, 80 and over, Alzheimer Disease/genetics/*metabolism, Antibodies, Monoclonal/*chemistry/immunology, Antibody Specificity, Blotting, Western, Enzyme-Linked Immunosorbent Assay, Epitopes, Female, Fluorescent Antibody Technique, Indirect, Human, Hybridomas, Immunohistochemistry, Male, Microscopy, Confocal, Middle Age, Neurofibrillary Tangles/metabolism/pathology, Protein Conformation, Support, U.S. Gov't, P.H.S., tau Proteins/chemistry/*immunology

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