Tissue-nonspecific Alkaline Phosphatase Promotes the Neurotoxicity Effect of Extracellular Tau
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 unmodifi...
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Published in | The Journal of biological chemistry Vol. 285; no. 42; pp. 32539 - 32548 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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United States
Elsevier Inc
15.10.2010
American Society for Biochemistry and Molecular Biology |
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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, activation of muscarinic receptors by dephosphorylated 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. |
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AbstractList | 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, activation of muscarinic receptors by dephosphorylated 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. |
Author | Avila, Jesús Miras-Portugal, M. Teresa Gómez-Villafuertes, Rosa Naranjo, José R. Díaz-Hernández, Miguel Gómez-Ramos, Alberto Rubio, Alicia |
Author_xml | – sequence: 1 givenname: Miguel surname: Díaz-Hernández fullname: Díaz-Hernández, Miguel organization: Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain – sequence: 2 givenname: Alberto surname: Gómez-Ramos fullname: Gómez-Ramos, Alberto organization: Centro de Biología Molecular “Severo Ochoa,” Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28049 Madrid, Spain – sequence: 3 givenname: Alicia surname: Rubio fullname: Rubio, Alicia organization: Centro de Biología Molecular “Severo Ochoa,” Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28049 Madrid, Spain – sequence: 4 givenname: Rosa surname: Gómez-Villafuertes fullname: Gómez-Villafuertes, Rosa organization: Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain – sequence: 5 givenname: José R. surname: Naranjo fullname: Naranjo, José R. organization: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain – sequence: 6 givenname: M. Teresa surname: Miras-Portugal fullname: Miras-Portugal, M. Teresa organization: Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain – sequence: 7 givenname: Jesús surname: Avila fullname: Avila, Jesús email: javila@cbm.uam.es organization: Centro de Biología Molecular “Severo Ochoa,” Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid, 28049 Madrid, Spain |
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Issue | 42 |
Keywords | Calcium Neurodegeneration Tau Calcium Homeostasis Alkaline Phosphatase Dephosphorylation Alzheimer Disease Phosphatase Extracellular Tau |
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SubjectTerms | Acetylcholine receptors (muscarinic) Aged Aged, 80 and over Alkaline Phosphatase Alkaline Phosphatase - metabolism Alzheimer Disease Alzheimer Disease - metabolism Alzheimer's disease Animals Brain Brain - enzymology Calcium Calcium (intracellular) Calcium - metabolism Calcium Homeostasis Cell Line, Tumor - drug effects Central nervous system Dephosphorylation Enzymes Extracellular levels Extracellular Tau Female Hippocampus Humans Male Mice Molecular Bases of Disease Neurobiology Neuroblastoma cells Neurodegeneration Neurodegenerative diseases Neurofibrillary tangles Neurons Neurotoxicity Phosphatase Tau Tau protein tau Proteins - pharmacology tau Proteins - toxicity Transcription |
Title | Tissue-nonspecific Alkaline Phosphatase Promotes the Neurotoxicity Effect of Extracellular Tau |
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