Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices

K. A. Harris, G. A. Oyler, G. M. Doolittle, I. Vincent, R. A.W. Lehman, R. L. Kincaid, M. L. Billingsley

Research output: Contribution to journalArticle

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Abstract

Hyperphosphorylated forms of the microtubule‐associated protein tau are components of the paired helical filaments (PHFs) seen in patients with Alzheimer's disease. Slices of human lateral temporal cortex were obtained from tissues removed incidental to resections for intractable hippocampal epilepsy. Tau phosphorylation in temporal lobe slices was determined using mobility shifts after sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and immunodetection with the monoclonal antibodies Alz‐50, 5E2, and Tau‐1. The results indicate that tau phosphorylation was altered in a dose‐dependent manner by the phosphatase inhibitor okadaic acid, but not by N‐methyl‐D‐aspartate, quisqualate, or kainate. The slowest mobility forms of tau, termed “PHF‐like tau,” produced by okadaic acid treatment were dephosphorylated by purified protein phosphatase 2B (calcineurin). Formation of PHF‐like tau peptides was blocked by KN‐62, 1{N,O‐bis(1,5‐isoquinolinesulfonyl)‐N‐methyl‐L‐tyrosyl}‐4‐phenylpiperazine, an inhibitor of Ca2+/calmodulin‐dependent protein kinase II. The protein kinase inhibitor staurosporine also prevented formation of PHF‐like tau. These data suggest that phosphorylation of tau is regulated by Ca2+‐dependent protein kinases and okadaic acid–sensitive protein phosphatases, alterations of which may be implicated in the pathogenesis of Alzheimer' disease.

Original languageEnglish (US)
Pages (from-to)77-87
Number of pages11
JournalAnnals of Neurology
Volume33
Issue number1
DOIs
StatePublished - Jan 1993

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Okadaic Acid
Calcineurin
Phosphorylation
Temporal Lobe
Protein Kinases
Alzheimer Disease
Brain
Quisqualic Acid
tau Proteins
Staurosporine
Kainic Acid
Phosphoprotein Phosphatases
Protein Kinase Inhibitors
Phosphoric Monoester Hydrolases
Electrophoresis
Gels
Sodium
Monoclonal Antibodies
Peptides
human MAPT protein

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Harris, K. A., Oyler, G. A., Doolittle, G. M., Vincent, I., Lehman, R. A. W., Kincaid, R. L., & Billingsley, M. L. (1993). Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. Annals of Neurology, 33(1), 77-87. https://doi.org/10.1002/ana.410330113
Harris, K. A. ; Oyler, G. A. ; Doolittle, G. M. ; Vincent, I. ; Lehman, R. A.W. ; Kincaid, R. L. ; Billingsley, M. L. / Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. In: Annals of Neurology. 1993 ; Vol. 33, No. 1. pp. 77-87.
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Harris, KA, Oyler, GA, Doolittle, GM, Vincent, I, Lehman, RAW, Kincaid, RL & Billingsley, ML 1993, 'Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices', Annals of Neurology, vol. 33, no. 1, pp. 77-87. https://doi.org/10.1002/ana.410330113

Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. / Harris, K. A.; Oyler, G. A.; Doolittle, G. M.; Vincent, I.; Lehman, R. A.W.; Kincaid, R. L.; Billingsley, M. L.

In: Annals of Neurology, Vol. 33, No. 1, 01.1993, p. 77-87.

Research output: Contribution to journalArticle

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Harris KA, Oyler GA, Doolittle GM, Vincent I, Lehman RAW, Kincaid RL et al. Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. Annals of Neurology. 1993 Jan;33(1):77-87. https://doi.org/10.1002/ana.410330113