S100beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease.
The zinc-binding protein S100beta has been identified as an interacting partner with the microtubule-associated protein tau. Both proteins are individually affected in Alzheimer's disease (AD). S100beta, 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 S100beta-associated cellular responses. Abnormally phosphorylated tau extracted from AD tissue displayed a dramatically reduced capacity to bind S100beta, which was restored by pretreatment with alkaline phosphatase. In differentiated SH-SY5Y cells, exogenous S100beta 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. S100beta uptake was also accompanied by extensive neurite outgrowth that may be mediated by its interaction with tau. S100beta-tau binding may represent a key pathway for neurite development, possibly through S100beta modulation of tau phosphorylation and/or functional stabilization of microtubules and process formation. S100beta-tau interaction may be disrupted by hyperphosphorylation and/or imbalances in zinc metabolism, and this may contribute to the neurite dystrophy associated with AD.
Centre for Research in Neurodegenerative Diseases, Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 3H2. haung.yu@utoronto.ca
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Yu
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Fraser
D000544:Alzheimer Disease / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D009414:Nerve Growth Factors / Q000378:metabolism*; D010766:Phosphorylation; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D015032:Zinc / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D016875:tau Proteins; D015032:Zinc