Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau

Miguel Díaz-Hernández, Alberto Gómez-Ramos, Alicia Rubio, Rosa Gómez-Villafuertes, José R. Naranjo, M. Teresa Miras-Portugal, Jesús Avila

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Abstract

There is solid evidence indicating that hyperphosphorylated tau protein, the main component of intracellular neurofibrillary tangles present in the brain of Alzheimer disease patients, plays a key role in progression of this disease. However, it has been recently reported that extracellular unmodified tau protein may also induce a neurotoxic effect on hippocampal neurons by activation of M1 and M3 muscarinic receptors. In the present work we show an essential component that links both effects, which is tissue-nonspecific alkaline phosphatase (TNAP). This enzyme is abundant in the central nervous system and is mainly required to keep control of extracellular levels of phosphorylated compounds. TNAP dephosphorylates the hyperphosphorylated tau protein once it is released upon neuronal death. Only the dephosphorylated tau protein behaves as an agonist of muscarinic M1 and M3 receptors, provoking a robust and sustained intracellular calcium increase finally triggering neuronal death. Interestingly,activationofmuscarinicreceptorsbydephosphorylated tau increases the expression of TNAP in SH-SY5Y neuroblastoma cells. An increase in TNAP activity together with increases in protein and transcript levels were detected in Alzheimer disease patients when they were compared with healthy controls.

Original languageEnglish
Pages (from-to)32539-32548
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number42
DOIs
Publication statusPublished - Oct 15 2010

Fingerprint

tau Proteins
Alkaline Phosphatase
Muscarinic M3 Receptors
Muscarinic M1 Receptors
Tissue
Alzheimer Disease
Neurofibrillary Tangles
Neurology
Brain Diseases
Neuroblastoma
Neurons
Disease Progression
Brain
Central Nervous System
Chemical activation
Calcium
Enzymes
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Díaz-Hernández, M., Gómez-Ramos, A., Rubio, A., Gómez-Villafuertes, R., Naranjo, J. R., Teresa Miras-Portugal, M., & Avila, J. (2010). Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. Journal of Biological Chemistry, 285(42), 32539-32548. https://doi.org/10.1074/jbc.M110.145003

Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. / Díaz-Hernández, Miguel; Gómez-Ramos, Alberto; Rubio, Alicia; Gómez-Villafuertes, Rosa; Naranjo, José R.; Teresa Miras-Portugal, M.; Avila, Jesús.

In: Journal of Biological Chemistry, Vol. 285, No. 42, 15.10.2010, p. 32539-32548.

Research output: Contribution to journalArticle

Díaz-Hernández, M, Gómez-Ramos, A, Rubio, A, Gómez-Villafuertes, R, Naranjo, JR, Teresa Miras-Portugal, M & Avila, J 2010, 'Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau', Journal of Biological Chemistry, vol. 285, no. 42, pp. 32539-32548. https://doi.org/10.1074/jbc.M110.145003
Díaz-Hernández M, Gómez-Ramos A, Rubio A, Gómez-Villafuertes R, Naranjo JR, Teresa Miras-Portugal M et al. Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. Journal of Biological Chemistry. 2010 Oct 15;285(42):32539-32548. https://doi.org/10.1074/jbc.M110.145003
Díaz-Hernández, Miguel ; Gómez-Ramos, Alberto ; Rubio, Alicia ; Gómez-Villafuertes, Rosa ; Naranjo, José R. ; Teresa Miras-Portugal, M. ; Avila, Jesús. / Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 42. pp. 32539-32548.
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