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. 2001 Oct 12;276(41):37967-73.
doi: 10.1074/jbc.M105365200. Epub 2001 Aug 8.

Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein

A D Alonso  1 , T Zaidi, M Novak, H S Barra, I Grundke-Iqbal, K Iqbal
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Free article

Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein

A D Alonso et al. J Biol Chem. .
Free article

Abstract

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 tau4L > tau4S > tau4 and tau3L > tau3S > tau3, and that its binding to tau4L was greater than to tau3L. 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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