Tau Phosphorylation Mechanisms in Neurodegenerative Diseases

Tau is a neuronal microtubule-associated protein that undergoes reversible phosphorylation at multiple serine, threonine and tyrosine residues. Under physiological conditions, this post-translational modification modulates tau’s affinity for microtubules and regulates axonal transport, synaptic function and cytoskeletal dynamics. In many neurodegenerative tauopathies, including Alzheimer’s disease, frontotemporal dementia and primary age-related tauopathy, an imbalance between kinase and phosphatase activities drives abnormal hyperphosphorylation of tau. Key kinases such as glycogen synthase kinase-3β, cyclin-dependent kinase 5 and microtubule affinity-regulating kinases add phosphate groups, whereas protein phosphatase 2A and related enzymes remove them. Excessive phosphorylation weakens tau–microtubule interactions, promotes misfolding and oligomerisation, and precipitates the formation of neurofibrillary tangles. These aggregates impair synaptic signalling, disrupt proteostasis and can spread pathology trans-synaptically. Recent mechanistic studies have also highlighted the role of specific phosphorylation sites in governing tau’s nuclear functions, interactions with chaperones and susceptibility to clearance pathways. A deeper understanding of the spatial and temporal sequence of tau phosphorylation events is central to designing targeted interventions that restore physiological tau function and arrest neurodegenerative progression.

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Tau Phosphorylation Mechanisms in Neurodegenerative Diseases publication trend

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Technical terms

Tau protein: A neuronal microtubule-associated protein involved in stabilising axonal cytoskeleton and regulating intracellular transport.

Phosphorylation: Covalent attachment of a phosphate group to amino acid side chains, often modulating protein activity and interactions.

Hyperphosphorylation: Excessive and aberrant phosphorylation that disrupts normal protein function and promotes aggregation.

Kinase: An enzyme that transfers phosphate groups from high-energy donors to specific substrates, such as tau.

Phosphatase: An enzyme that removes phosphate groups, restoring proteins to their dephosphorylated state.

Neurofibrillary tangle: Insoluble aggregates of hyperphosphorylated tau found within neurons in various tauopathies.

Oligomerisation: Assembly of protein monomers into small, soluble aggregates that can be neurotoxic.

References

1. Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer’s disease and related tauopathies. Science Bulletin (2024).
2. p-tau Ser356 is associated with Alzheimer’s disease pathology and is lowered in brain slice cultures using the NUAK inhibitor WZ4003. Acta Neuropathologica (2024).
3. Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials. Molecular Psychiatry (2023).