| * Tau, a microtubule-associated protein expressed predominantly in neurons, belongs to a family of microtubule-stabilizing proteins that regulate cytoskeletal dynamics through isoform-specific binding to tubulin polymers. Alternative splicing of the MAPT gene produces six isoforms distinguished by N-terminal inserts, and either three or four microtubule-binding repeats in the C-terminal region, enabling differential affinity for microtubules under varying phosphorylation states. Hyperphosphorylation at multiple sites by kinases, including GSK-3β, CDK5, and ERK1/2, reduces tau's affinity for microtubules, promoting its detachment and subsequent aggregation into paired helical filaments that form neurofibrillary tangles. Tau stabilizes axonal microtubules to facilitate axonal transport of vesicles, mitochondria, and signaling molecules, with isoform balance maintaining neuronal polarity and synaptic integrity. Pathological hyperphosphorylation disrupts this stabilization, leading to microtubule disassembly, impaired trafficking, and accumulation of tau oligomers that impair synaptic function and propagate prion-like across neurons. Tau interacts with heat shock proteins such as Hsc70, which engage soluble tau following microtubule destabilisation, modulating its conformation and preventing aggregation. In Alzheimer's disease and related tauopathies, insoluble tau filaments correlate with neuronal loss and cognitive decline, and tangle pathology spreads from the entorhinal cortex to the hippocampus and neocortex. |
