Tau protein promotes microtubule assembly and stability. Tau is also involved in the establishment and maintenance of neural polarity. The C-terminus domain of Tau binds to axonal microtubules whereas the N-terminus domain binds to neural plasma membrane components, therefore suggesting that Tau protein functions as a linker between the two. Axonal polarity is predetermined by tau localization in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization. PNS-tau is expressed in the peripheral nervous system whereas the other isoforms are expressed in the central nervous system. Defects in Tau protein are a cause of dementia, parkinsonism and Alzheimer disease. It has been well documented that hyperphosphorylated tau is a major component of paired helical filaments in AD brain. Serine 416 has been demonstrated to be a major phosphorylation site in vitro by CaM kinase II.