Figure 1

Tau-mediated neurodegeneration. Physiologically tau protein can bind and thereby stabilize microtubules (MTs). The attachment of tau to MT is regulated by its phosphorylation level. Phosphorylation of tau mediated by kinase (Cdk5, GSK3β, MARK and ERK2) may lead to the detachment of tau from MT and hereby cause MT depolymerization. Conversely, phosphatase (PP1, PP2A, PP2B and PP2C) will reduce the phosphorylation level of tau and restore the binding ability of tau for MT. Such equilibrium between the roles of kinases and phosphatases is disrupted under pathological condition, and increase in the kinase activity and decrease in the phosphatase activity will cause tau hyperphosphoryation. Hyperphosphorylated tau protein is misfolded and forms β-sheet-containing structure paired helical filaments (PHFs). These structure transitions will lead to more organized aggregates, and eventually develop neurofibrillary tangles (NFT) inside neurons. NFT will impair normal axonal transport, disrupt synaptic plasticity, and finally induce cell loss.