Areal and Subcellular Localization of the Ubiquitous Alkaline Phosphatase in the Primate Cerebral Cortex: Evidence for a Role in Neurotransmission

Fonta, Caroline; Négyessy, László; Renaud, Luc; Barone, Pascal

doi:10.1093/cercor/bhh021

Cited by 86 publications

(127 citation statements)

References 101 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…2, E and F), demonstrating that intracellular tau undergoes a broad dephosphorylation once it is present at the extracellular medium likely due to the action of cell membrane phosphatases. A well known example of these enzymes is TNAP, which is located not only in the cytosol but also in the membrane of neuronal cells (26).…”

Section: Resultsmentioning

confidence: 99%

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

Dı́az-Hernández

Gómez-Ramos

Rubio

et al. 2010

Journal of Biological Chemistry

136

139

View full text Add to dashboard Cite

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. Alzheimer disease (AD)3 is characterized by the loss of neurons and the presence of amyloid plaques and neurofibrillary tangles. The plaques are dense deposits of amyloid-␤ peptide and cellular material outside and around neurons, whereas the tangles are aggregates of the microtubule-associated protein tau, which has become hyperphosphorylated and accumulates inside the cells (1). In AD, tau pathology follows a reproducible pattern, in which hyperphosphorylated and aggregated tau first appears in the entorhinal cortex and hippocampus, and from there the disease spreads to the surrounding areas (2). During this process, neuronal loss occurs and tau protein may be found in the extracellular space in monomeric form or in aggregated form, assembled in extracellular ghost tangles. Indeed, an inverse correlation can be found between the number of extracellular tangles and the number of living neurons in the hippocampus (3-5). It has been also suggested that extracellular aggregated tau can promote the aggregation of intracellular tau (6). Moreover, it has been reported that extracellular monomeric tau is toxic for neurons, playing a role in the spreading of AD pathology (7-9). Monomeric tau-dependent toxicity occurs when extracellular tau binds and activates cell membrane receptors, identified as M1 and M3 muscarinic receptors (7).Sluggish disassembly of aggregated tau and slow degradation of its monomeric form in extracellular media provide this protein with a long stay outside the cell. In this location, hyperphosphorylated monomeric tau can be recognized as a substrate of several extracellular enzymes, some of which can remove the phosphates from the protein (10, 11). One of these enzymes is tissue-nonspecific alkaline phosphatas...

show abstract

Section: Resultsmentioning

confidence: 99%

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

Dı́az-Hernández

Gómez-Ramos

Rubio

et al. 2010

Journal of Biological Chemistry

136

139

View full text Add to dashboard Cite

show abstract

“…Knockout mice have elucidated the role of TNSALP in the central nervous system. TNSALP not only has a role in GABA neurotransmission but was found in the synaptic cleft of primary sensory areas (Fonta et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Infantile Hypophosphatasia Secondary to a Novel Compound Heterozygous Mutation Presenting with Pyridoxine-Responsive Seizures

et al. 2013

View full text Add to dashboard Cite

Hypophosphatasia (HPP) is a rare metabolic disease with the hallmark finding of deficient serum tissue nonspecific alkaline phosphatase (TNSALP) activity. TNSALP is primarily known for its role in mineralization; hence, HPP is characterized by defective mineralization of bone and/or teeth. TNSALP is also necessary for proper vitamin B6 metabolism and its participation as a cofactor for neurotransmitters in the central nervous system. Defective TNSALP activity in the brain can result in intractable seizures responsive to pyridoxine. The pathophysiology of pyridoxine-responsive seizures (PRS) in severe HPP remains to be clearly defined. We review the case of a 2-month-old Caucasian boy presenting with seizures refractory to conventional antiepileptic medications. Empiric treatment with favorable response to pyridoxine in conjunction with severe metabolic bone disease, extremely low serum alkaline phosphatase, elevated phosphoethanolamine, hypercalcemia, hypercalciuria, and nephrocalcinosis led to a clinical diagnosis of infantile HPP. Sequence analysis revealed compound heterozygosity of the TNSALP gene with a novel mutation in exon 9 and a previously reported mutation in exon 12. This case reminds the physician that severe infantile HPP can present with PRS as its major initial manifestation and should alert clinicians to consider HPP in their differential of PRS. In addition, despite this severe genotype, the clinical diagnosis of our patient was delayed because of minimal phenotypic features initially. This highlights that the phenotypegenotype correlation could be variable even in severe disease. This case also demonstrates that HPP should be classified as PRS and not a form of pyridoxine-dependent epilepsy (PDE) as our patient was able to stop the pyridoxine supplementation without seizure recurrence once enzyme replacement was initiated. With the advent of enzyme replacement therapy, this once fatal disease may have improved morbidity and mortality.

show abstract

“…The involvement of pyridoxal phosphatase/chronophin was mentioned earlier. It is interesting that alkaline phosphatase activity has also been associated with activity dependent functions in the cortex (Fonta et al 2004). …”

Section: Long Term Potentiationmentioning

confidence: 99%

Vitamin B-6 Metabolism and Interactions with TNAP

Coburn

2015

Subcellular Biochemistry

View full text Add to dashboard Cite

Areal and Subcellular Localization of the Ubiquitous Alkaline Phosphatase in the Primate Cerebral Cortex: Evidence for a Role in Neurotransmission

Cited by 86 publications

References 101 publications

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

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

Infantile Hypophosphatasia Secondary to a Novel Compound Heterozygous Mutation Presenting with Pyridoxine-Responsive Seizures

Vitamin B-6 Metabolism and Interactions with TNAP

Contact Info

Product

Resources

About