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

The microtubule-associated protein tau is a family of six isoforms that bec omes abnormally hyperphosphorylated and accumulates in neurons undergoing n eurodegeneration in the brains of patients with Alzheimer disease (AD). We investigated the isoform-specific interaction of normal tau with AD hyperph osphorylated tau (AD P-tau). We found that the binding of AD P-tau to norma l human recombinant tau was tau 4L > tau 4S > tau4 and tau 3L > tau 3S > ta u3, and that its binding to tau 4L was greater than to tau 3L. AD P-tau als o inhibited the assembly of microtubules promoted by each tau isoform and c aused 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 cha racteristics. Like AD P-tau, P-tau interacted with and sequestered normal t au and inhibited microtubule assembly. These studies suggest that the AD P- tau interacts preferentially with the tau isoforms that have the amino-term inal inserts and four microtubule binding domain repeats and that hyperphos phorylation of tau appears to be sufficient to acquire AD P-tau characteris tics. Thus, lack of amino-terminal inserts and extra microtubule binding do main repeat in fetal human brain might be protective from Alzheimer's neuro fibrillary degeneration.