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The Journal of Neuroscience, April 1, 2001, 21(7):2240-2246

S100 Interaction with Tau Is Promoted by Zinc and Inhibited by Hyperphosphorylation in Alzheimer's Disease

W. Haung Yu^{1, 2} and Paul E. Fraser^{1, 3}

¹ Centre for Research in Neurodegenerative Diseases, ² Department of Pharmacology, and ³ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5S 3H2

The zinc-binding protein S100 has been identified as an interacting partner with the microtubule-associated protein tau. Both proteins are individually affected in Alzheimer's disease (AD). S100, is overexpressed in the disease, whereas hyperphosphorylated tau constitutes the primary component of neurofibrillary tangles. In this study, we examine factors that modulate their binding and the potential role the complex may play in AD pathogenesis. Zinc was identified as a critical component in the binding process and a primary modulator of S100-associated cellular responses. Abnormally phosphorylated tau extracted from AD tissue displayed a dramatically reduced capacity to bind S100, which was restored by pretreatment with alkaline phosphatase. In differentiated SH-SY5Y cells, exogenous S100 was internalized and colocalized with tau consistent with an intracellular association. This was enhanced by the addition of zinc and eliminated by divalent metal chelators. S100 uptake was also accompanied by extensive neurite outgrowth that may be mediated by its interaction with tau. S100-tau binding may represent a key pathway for neurite development, possibly through S100 modulation of tau phosphorylation and/or functional stabilization of microtubules and process formation. S100-tau interaction may be disrupted by hyperphosphorylation and/or imbalances in zinc metabolism, and this may contribute to the neurite dystrophy associated with AD.

Key words: S100; tau; Alzheimer's disease; zinc; binding; colocalization; neuronal development

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2172240-07$05.00/0

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