Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain
Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing 100875, ChinaBrain research bulletin (Impact Factor: 2.72). 08/2008; 76(5):464-468. DOI: 10.1016/j.brainresbull.2007.12.005
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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- "Members of the highly conserved FKBP family are found throughout the nervous system and have been well studied in the context of steroid hormone complexes and AD biology (Steiner et al. 1992). These chaperones bind to the immunosuppressive drug FK-506, which has been shown to regulate tau and Ab in vivo (Zhao et al. 2006; Yoshiyama et al. 2007; Luo et al. 2008; Dineley et al. 2010). These studies revealed that FK-506 reduced tau and Ab pathology in the P301S mouse and Ab oligomer-treated mice, respectively (Yoshiyama et al. 2007; Dineley et al. 2010). "
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 · 4.28 Impact Factor
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ABSTRACT: Calcineurin, an important protein Ser/Thr phosphatase which acts on tau in vivo, is a heterodimer of a catalytic subunit, calcineurin A, and a regulatory subunit, calcineurin B, and is unique in being regulated by calmodulin. Here, we find that both subunits of calcineurin bind tau, and calmodulin interferes with the association between calcineurin and tau. The domains of both subunits of calcineurin and tau involved in binding are mapped. We also investigate the functional consequences of the interactions between both subunits of calcineurin, tau and calmodulin, and reveal the interactions affect dephosphorylation of tau by calcineurin and contribute to the balance of phosphorylation and dephosphorylation of tau in vivo. Our findings may be of potential significance in neuronal physiology and also in neurodegenerative disorders. They shed some light on how the interactions might control the phosphorylation state of tau under physiological conditions, and provide new insights into the treatment of tauopathies such as Alzheimer's disease.Biochimica et Biophysica Acta 12/2008; 1783(12):2255-61. DOI:10.1016/j.bbamcr.2008.06.015 · 4.66 Impact Factor
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