TNAP Plays a Key Role in Neural Differentiation as well as in Neurodegenerative Disorders.

New evidences have been reported that point to the ecto-enzyme, tissue-nonspecific alkaline phosphatase (TNAP), as a key element at the origin of two opposite phenomena, neuronal differentiation and neuronal degeneration. During brain development, TNAP plays an essential role for establishing neuronal circuits. The pro-neuritic effect induced by TNAP, which results in axonal length increase, is due to its enzymatic hydrolysis of extracellular ATP at the surrounding area of the axonal growth cone . In this way, the activation of P2X7 receptor is prevented and as a consequence there is no inhibition of axonal growth. The existence of a close functional interrelation between both purinergic elements is finally supported by the fact that both elements may control, in a reciprocal way, the expression level of the other. On the opposite stage, recent evidences indicate that TNAP plays a key role in spreading the neurotoxicity effect induced by extracellular hyperphosphorylated tau protein, the main component of intracellular neurofibrillary tangles present in the brain of Alzheimer disease patients. TNAP exhibits a broad substrate specificity and in addition to nucleotides it is able to dephosphorylate extracellular proteins, such as the hyperphosphorylated tau protein once it is released to the extracellular medium. Dephosphorylated tau protein behaves as an agonist of muscarinic M1 and M3 receptors, provoking a robust and sustained intracellular calcium increase that finally triggering neuronal death. Besides, activation of muscarinic receptors by dephosphorylated tau increases the expression of TNAP, which could explain the increase in TNAP activity and protein levels detected in Alzheimer disease.