Tissue-nonspecific Alkaline Phosphatase Promotes the Neurotoxicity Effect of Extracellular Tau

• Published in: The Journal of biological chemistry Vol. 285; no. 42; pp. 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: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2010; American Society for Biochemistry and Molecular Biology
• 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; Transcription; Calcium; Neurodegeneration; Tau; Calcium Homeostasis; Alkaline Phosphatase; Dephosphorylation; Alzheimer Disease; Phosphatase; Extracellular Tau
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.145003

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.