Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain

Luo, Jing; Ma, Jie; Yu, Dayu; Bu, Fan; Zhang, Wen; Tu, Ling-Hui; Wang, Qun

doi:10.1016/j.brainresbull.2007.12.005

Cited by 22 publications

(13 citation statements)

References 21 publications

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“…Thus, we were interested in studying the effects of calcineurin expression and function in a cell model of tau metabolism. The effects of calcineurin on tau phosphorylation and the subsequent effects on microtubule binding have been described previously in cell and mouse models (Garver, et al, 1999, Luo, et al, 2008, Yu, et al, 2006b). We were interested in using a cell culture system to model changes in CSF ptau181 (Cruchaga, et al, 2010).…”

Section: Resultsmentioning

confidence: 75%

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Calcium phosphatase calcineurin influences tau metabolism

Karch

Jeng

Goate

2013

Neurobiology of Aging

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Alzheimer’s disease (AD) is characterized by neuronal loss and the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. Cerebrospinal fluid (CSF) levels of β-amyloid and tau/ptau181 are also associated with AD. We have previously demonstrated that a single nucleotide polymorphism in calcineurin is associated with CSF ptau181 levels and AD progression. In this study, we demonstrate that calcineurin protein levels are inversely correlated with dementia severity and Braak tangle stage in AD brains, and calcineurin activity is globally reduced in AD brains. We then sought to model the observed changes in CSF tau by measuring extracellular tau in cultured cells. SH-SY5Y cells treated with calcineurin inhibitors produced reduced calcineurin activity and a corresponding increase in extracellular ptau181. These findings are consistent with our observations in AD patients, who have elevated CSF ptau181 and reduced calcineurin activity in brain extracts. Thus, we have identified a gene that contributes to AD pathology and has functional consequences on tau metabolism in cultured cells.

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Section: Resultsmentioning

confidence: 75%

“…CsA and FK506 reduce calcineurin activity (Fig. 6A) via alternate mechanisms without altering calcineurin protein levels (Luo, et al, 2008, Yu, et al, 2006b). CsA binds to cyclophylin and the resulting complex blocks calcineurin activity, while FK506 interacts with the FK506 binding protein to inhibit calcineurin activity.…”

Section: Resultsmentioning

confidence: 99%

Calcium phosphatase calcineurin influences tau metabolism

Karch

Jeng

Goate

2013

Neurobiology of Aging

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“…Together with protein phosphatase 2A, Cn is normally responsible for the dephosphorylation of protein. This feature is illustrated by observations that tacrolimus induces hyperphosphorylation in mouse brain (30 ), whereas phosphorylation balance is maintained by counteracting kinases. Specific parts of the postmortem cerebral cortex of AD patients, however, show reductions in Cn activity that correlate with tangle formation (31 ).…”

Section: Brainmentioning

confidence: 98%

“…The protein, another direct substrate of Cn and a useful biomarker of AD, can be detected in cerebrospinal fluid (121 ). Given that the presence of single-nucleotide polymorphisms in the genes encoding the subunits of Cn is associated with altered and mRNA concentrations in cerebrospinal fluid (122 ) and that the infusion of CnIs into mouse brain induces hyperphosphorylated (30 ), status may reflect Cn signaling. Nuclear factor B is another transcription factor that can be activated by Cn (123 ).…”

Section: Calcineurin Assaysmentioning

confidence: 99%

Molecular Diagnostics of Calcineurin-Related Pathologies

Musson

Cobbaert²,

Smit³

2012

Clinical Chemistry

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BACKGROUND The Ca2+-dependent protein phosphatase enzyme calcineurin (Cn) (protein phosphatase 3) is best known for its role as director of the adaptive immune response. One of its principal substrates is the nuclear factor of activated T cells (NFAT), which translocates to the nucleus after dephosphorylation to mediate gene transcription. Drugs targeting Cn (the Cn inhibitors tacrolimus and cyclosporin A) have revolutionized posttransplantation therapy in allograft recipients by considerably reducing rejection rates. CONTENT Owing primarily to intensive study of the side effects of the Cn inhibitors, the unique importance of Cn and Cn/NFAT signaling in the normal physiological processes of many other cell and tissue types is becoming more evident. During the last decade, it has become clear that an extensive and diverse array of clinical conditions can be traced back, at least in part, to a disturbed Cn-signaling axis. Hence, both diagnostics and therapeutic monitoring could benefit from a technique that conveniently reads out Cn/NFAT operative status. SUMMARY This review outlines the current knowledge on the pathologic conditions that have calcineurin as a common denominator and reports on the progress that has been made toward successfully applying Cn and Cn/NFAT activity markers in molecular diagnostics.

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“…110,111 In contrast, downregulation of PP2B using antisense oligonucleotides or the inhibitors cyclosporin or FK506 resulted in increased phosphorylation of a number of sites in tau that are implicated in formation of NFTs. 35–37 Given that PP2B can directly dephosphorylate some of the same sites in vitro that are altered by PP2B inhibitors, the simplest explanation of these results is that PP2B directly can dephosphorylate certain sites in tau in vivo . However, PP2B, like other PPases, may also act indirectly to control the activities of the kinases that phosphorylate tau.…”

Section: Protein Phosphatase 2b (Calcineurin)mentioning

confidence: 99%

Protein Phosphatases and Alzheimer's Disease

Braithwaite

Stock

Lombroso

et al. 2012

Progress in Molecular Biology and Translational Science

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Alzheimer’s Disease (AD) is characterized by progressive loss of cognitive function, linked to marked neuronal loss. Pathological hallmarks of the disease are the accumulation of the amyloid-β (Aβ) peptide in the form of amyloid plaques and the intracellular formation of neurofibrillary tangles (NFTs). Accumulating evidence supports a key role for protein phosphorylation in both the normal and pathological actions of Aβ as well as the formation of NFTs. NFTs contain hyperphosphorylated forms of the microtubule-binding protein tau, and phosphorylation of tau by several different kinases leads to its aggregation. The protein kinases involved in the generation and/or actions of tau or Aβ are viable drug targets to prevent or alleviate AD pathology. However, it has also been recognized that the protein phosphatases that reverse the actions of these protein kinases are equally important. Here, we review recent advances in our understanding of serine/threonine and tyrosine protein phosphatases in the pathology of AD.

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Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain

Cited by 22 publications

References 21 publications

Calcium phosphatase calcineurin influences tau metabolism

Calcium phosphatase calcineurin influences tau metabolism

Molecular Diagnostics of Calcineurin-Related Pathologies

Protein Phosphatases and Alzheimer's Disease

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