Tau is a heterogeneous microtubule-associated protein that promotes and stabilizes microtubule assembly, especially in axons. Six isoforms with different amino-terminal inserts and different numbers of tandem repeats near the carboxy-terminus have been identified, and tau is hyperphosphorylated at approximately 25 sites by ERK, GSK-3 and CDK5. Phosphorylation decreases the ability of tau to bind to microtubules. Neurofibrillary tangles are a major hallmark of Alzheimer's disease and these tangles are bundles of paired helical filaments composed of hyperphosphorylated tau. In particular, phosphorylation of Ser396 by GSK-3 or CDK5 destabilizes microtubules in Alzheimer's disease. Furthermore, inclusions of tau are found in a number of other neurodegenerative diseases, collectively known as tauopathies.