Abstract
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.
Highlights
The zinc-binding protein S100 has been identified as an interacting partner with the microtubule-associated protein tau
High-affinity S100-associated proteins were removed by the addition of zinc chelators, which caused a structural rearrangement of S100
Our findings demonstrate that S100 binds to tau
Summary
The zinc-binding protein S100 has been identified as an interacting partner with the microtubule-associated protein tau. S100 overexpression in AD has been directly correlated with plaque-associated dystrophic neurite development and the astrocyte activation, as well as S100 overproduction, may be a direct effect of the loss of neuronal connections and amyloid- deposition (Van Eldik and Griffin, 1994; Mrak et al, 1996; Sheng et al, 2000). S100 has been shown to directly affect tau, for example, by its ability to block PKC phosphorylation at specific sites (Ser 262 and 313) (Biernat et al, 1992; Lin et al, 1994; Singh et al, 1996a) This activity may have a direct consequence for AD because loss of PKC phosphorylation increases the susceptibility of tau to hyperphosphorylation by GSK-3 (Singh et al, 1996b; Tsujo et al, 2000). Zinc has been implicated in some aspects of AD pathology, such as promotion of amyloid fibril formation (Bush et al, 1994) and, when examined in the current system, it
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