Figure 1.

Schematic representation illustrating the involvement of TNAP in the progression of Alzheimer’s disease. (A) Under physiological conditions, a moderate amount of tau protein can reach the interstitial space by different mechanisms. (B) As a consequence of an initial undetermined event, an unusual neuronal activity is induced, increasing tau secretion into the extracellular space. At this location, tau is dephosphorylated by TNAP becoming an active ligand of muscarinic receptors. The activation of muscarinic receptors by tau has four main consequences: First, a sustained increase in intracellular calcium levels that could compromise intracellular calcium homeostasis; Second, an increase of intracellular tau phosphorylation favoring the formation of NFTs; Third, higher expression levels of TNAP; Finally, possible receptor internalization following tau-induced muscarinic receptor activation. As result of these events, tau secretion would be increased, generating a positive feedback loop at the presynaptic level that finally leads to synaptic dysfunction. In the meantime, at the postsynaptic level, internalization of extracellular tau protein would take place. (C) As a result of this vicious cycle, neuronal functionality could be compromised, causing the rupture of the plasma membrane of the presynaptic neuron, with release of its intracellular content, including the NFTs, into the interstitial space. Since NFTs will undergo a slow disassembly and degradation, they will behave as new sources of extracellular tau, promoting the postsynaptic uptake of extracellular tau and the generation of NFTs at postsynaptic level. Finally, this event will stimulate the phosphorylation of intracellular tau resulting in a higher tau secretion also in the postsynaptic neuron, thus favoring the vicious cycle described above and the spreading of the disease.