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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Bibliographic Details
Published in:The Journal of biological chemistry 2010-10, Vol.285 (42), p.32539-32548
Main Authors: Díaz-Hernández, Miguel, Gómez-Ramos, Alberto, Rubio, Alicia, Gómez-Villafuertes, Rosa, Naranjo, José R., Miras-Portugal, M. Teresa, Avila, Jesús
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.145003