S100 beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease

The zinc-binding protein S100 beta has been identified as an interacting pa rtner with the microtubule-associated protein tau. Both proteins are indivi dually affected in Alzheimer's disease (AD). S100 beta, is overexpressed in the disease, whereas hyperphosphorylated tau constitutes the primary compo nent of neurofibrillary tangles. In this study, we examine factors that mod ulate their binding and the potential role the complex may play in AD patho genesis. Zinc was identified as a critical component in the binding process and a primary modulator of S100 beta -associated cellular responses. Abnor mally phosphorylated tau extracted from AD tissue displayed a dramatically reduced capacity to bind S100 beta, which was restored by pretreatment with alkaline phosphatase. In differentiated SH-SY5Y cells. exogenous S100 beta was internalized and colocalized with tau consistent with an intracellular association. This was enhanced by the addition of zinc and eliminated by d ivalent metal chelators. S100 beta uptake was also accompanied by extensive neurite outgrowth that may be mediated by its interaction with tau. S100 b eta -tau binding may represent a key pathway for neurite development, possi bly through S100 beta modulation of tau phosphorylation and/or functional s tabilization of microtubules and process formation. S100 beta -tau interact ion may be disrupted by hyperphosphorylation and/or imbalances in zinc meta bolism, and this may contribute to the neurite dystrophy associated with AD .