Abnormal Phosphorylation of the Microtubule-Associated Protein τ (Tau) in Alzheimer Cytoskeletal Pathology

• Published in: Proceedings of the National Academy of Sciences - PNAS 1986-07, Vol.83 (13), p.4913-4917
• Main Authors: Grundke-Iqbal, Inge, Iqbal, Khalid, Tung, Yunn-Chyn, Quinlan, Maureen, Wisniewski, Henryk M., Binder, Lester I.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Antibodies; Antibodies, Monoclonal; Antiserum; Biological and medical sciences; Cytoskeleton - ultrastructure; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia; Epitopes; Hippocampus - metabolism; Hippocampus - pathology; Humans; Immunologic Techniques; Medical sciences; Microtubule associated proteins; Microtubule-Associated Proteins - immunology; Microtubule-Associated Proteins - metabolism; Microtubules; Monoclonal antibodies; Neurites; Neurology; Phosphatases; Phosphoproteins - immunology; Phosphoproteins - metabolism; Phosphorylation; tau Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.83.13.4913

A monoclonal antibody to the microtubule-associated protein τ (tau) labeled some neurofibrillary tangles and plaque neurites, the two major locations of paired-helical filaments (PHF), in Alzheimer disease brain. The antibody also labeled isolated PHF that had been repeatedly washed with NaDodSO4. Dephosphorylation of the tissue sections with alkaline phosphatase prior to immunolabeling dramatically increased the number of tangles and plaques recognized by the antibody. The plaque core amyloid was not stained in either dephosphorylated or nondephosphorylated tissue sections. On immunoblots PHF polypeptides were labeled readily only when dephosphorylated. In contrast, a commercially available monoclonal antibody to a phosphorylated epitope of neurofilaments that labeled the tangles and the plaque neurites in tissue did not label any PHF polypeptides on immunoblots. The PHF polypeptides, labeled with the monoclonal antibody to τ , electrophoresed with those polypeptides recognized by antibodies to isolated PHF. The antibody to τ -labeled microtubules from normal human brains assembled in vitro but identically treated Alzheimer brain preparations had to be dephosphorylated to be completely recognized by this antibody. These findings suggest that τ in Alzheimer brain is an abnormally phosphorylated protein component of PHF.