Figure 7. A schematic representation of the vicious cycle leading to the amplification of tau secretion in AD.

In AD, tau becomes hyperphosphorylated (1). This hyperphosphorylation would enhance its secretion by either exosomes/microvesicles or another unconventional secretory pathway (2). Extracellular hyperphosphorylated tau would be dephosphorylated by TNAP present at the plasma membrane (3) and this would result in an increase of dephosphorylated tau in the extracellular space (4). Dephosphorylated extracellular tau would activate the muscarinic receptors (5) and this would induce an increase of intracellular calcium (6), an event linked to the increase of tau hyperphosphorylation (7). This further increase of hyperphosphorylated tau would initiate a vicious circle that would enhance tau secretion.