Amyloid plaques, neurofibrillary tangles (NFTs), and neuronal loss are the major pathological hallmarks of Alzheimer’s disease (AD). NFTs are intracellular aggregates of hyperphosphorylated Tau. Tau is a highly soluble, unfolded microtubule-associated protein (MAP) that regulates microtubule dynamics and reorganization. It is abundant in the central nervous system, specifically in the axons of mature neurons, where it regulates axon elongation, maturation, and transport.
Tau is a phosphoprotein that, under physiological conditions, has about 30 of its available 79 Ser and Thr phosphorylation sites phosphorylated. A multitude of kinases phosphorylate Tau including GSK-3 beta, CDK5, and PKA. On the other hand, only a small number of phosphatases, such as PP2A and Calcineurin A, dephosphorylate Tau. In AD and other tauopathies, Tau becomes hyperphosphorylated; however, the causes leading to abnormal Tau hyperphosphorylation are still not fully understood.
Hyperphosphorylated Tau is thought to exert its pathological effects by several mechanisms. As previously stated, hyperphosphorylation of Tau causes it to transform into PHF-Tau (paired helical filament) and NFTs. Phosphorylated Tau also detaches from microtubules and is aberrantly trafficked from axons to the cell body and dendrites, where is aggregates and interferes with normal synaptic transmission. Additionally, hyperphosphorylated Tau impairs proteosomal degradation and autophagy, thereby inhibiting Tau turnover. R&D Systems offers a range of research tools for investigating Tau phosphorylation and NFT formation.