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J. Biol. Chem., Vol. 276, Issue 41, 37967-37973, October 12, 2001

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Interaction of Tau Isoforms with Alzheimer's Disease Abnormally Hyperphosphorylated Tau and in Vitro Phosphorylation into the Disease-like Protein^*

Alejandra del C. Alonso, Tanweer Zaidi, Michal Novak^§, Hector S. Barra^¶, Inge Grundke-Iqbal, and Khalid Iqbal

From the  New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, ^¶ Departmento de Química Biológica, Facultad de Ciencias Químicas, Centro de Investigaciones en Química Biológica de Córdoba-CONICET, Córdoba 5000, Argentina, and ^§ Institute of Neuroimmunology, Slovak Academy of Sciences, Dubrovdka cesta 9, Bratislava 842 46, Slovak Republic

The microtubule-associated protein tau is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in neurons undergoing neurodegeneration in the brains of patients with Alzheimer disease (AD). We investigated the isoform-specific interaction of normal tau with AD hyperphosphorylated tau (AD P-tau). We found that the binding of AD P-tau to normal human recombinant tau was 4L > 4S > 4 and 3L > 3S > 3, and that its binding to 4L was greater than to 3L. AD P-tau also inhibited the assembly of microtubules promoted by each tau isoform and caused disassembly when added to preassembled microtubules. This inhibition and depolymerization of microtubules by the AD P-tau corresponded directly to the degree of its interaction with the different tau isoforms. In vitro hyperphosphorylation of recombinant tau (P-tau) conferred AD P-tau-like characteristics. Like AD P-tau, P-tau interacted with and sequestered normal tau and inhibited microtubule assembly. These studies suggest that the AD P-tau interacts preferentially with the tau isoforms that have the amino-terminal inserts and four microtubule binding domain repeats and that hyperphosphorylation of tau appears to be sufficient to acquire AD P-tau characteristics. Thus, lack of amino-terminal inserts and extra microtubule binding domain repeat in fetal human brain might be protective from Alzheimer's neurofibrillary degeneration.

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