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

Research output: Contribution to journalArticlepeer-review


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
Issue number42
Publication statusPublished - Oct 15 2010

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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