Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain
ABSTRACT Calcineurin is a Ca2+/calmodulin-dependent protein phosphatase expressed at high levels in brain. Many electrophysiological and pharmacological findings have shown that calcineurin plays an important role in brain function. FK506 is always used as a specific calcineurin inhibitor in these researches. But these reports did not quantify the calcineurin activity in FK506-treated brain. Here we first investigated the inhibitory effect of FK506 injected into the mouse brain ventricle on CN activity. FK506 reduced calcineurin activity in a dose-dependent manner, without affecting its amount. Injection of 12.5 nmol FK506 also significantly enhanced the phosphorylation of tau at Ser-262 (12E8 site), Ser-198, Ser-199, and/or Ser-202 (Tau-1 site) and Ser-396 and/or Ser-404 (PHF-1 site), without affecting total tau. It is suggested that calcineurin plays an important role in tau phosphorylation, dependently of its activity. Compared with the effects of cyclosporin A, another specific inhibitor of CN in our previous study, we first evaluate that such infusion of FK506 is more effective than that of cyclosporin A on calcineurin inhibition and tau phosphorylation.
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ABSTRACT: Peptidyl-prolyl cis/trans isomerases (PPIases), a unique family of molecular chaperones, regulate protein folding at proline residues. These residues are abundant within intrinsically disordered proteins, like the microtubule-associated protein tau. Tau has been shown to become hyperphosphorylated and accumulate as one of the two main pathological hallmarks in Alzheimer's disease (AD), the other being amyloid beta (Aβ). PPIases, including Pin1, FK506-binding protein (FKBP) 52, FKBP51, and FKBP12, have been shown to interact with and regulate tau biology. This interaction is particularly important given the numerous proline-directed phosphorylation sites found on tau and the role phosphorylation has been found to play in pathogenesis. This regulation then affects downstream aggregation and oligomerization of tau. However, many PPIases have yet to be explored for their effects on tau biology, despite the high likelihood of interaction based on proline content. Moreover, Pin1, FKBP12, FKBP52, cyclophilin (Cyp) A, CypB, and CypD have been shown to also regulate Aβ production or the toxicity associated with Aβ pathology. Therefore, PPIases directly and indirectly regulate pathogenic protein multimerization in AD and represent a family rich in targets for modulating the accumulation and toxicity.This article is protected by copyright. All rights reserved.Journal of Neurochemistry 01/2015; 133(1). DOI:10.1111/jnc.13033 · 4.24 Impact Factor
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