Tau Pathology in Neurodegenerative Disease Mechanisms

Tau is a microtubule-associated protein that stabilises neuronal cytoskeletal architecture under physiological conditions. In neurodegenerative disorders known as tauopathies, aberrant post-translational modifications—most notably hyperphosphorylation—trigger tau detachment from microtubules, misfolding and self-assembly into soluble oligomers and insoluble neurofibrillary tangles. These aggregates disrupt axonal transport, synaptic integrity and mitochondrial function, culminating in neuronal dysfunction and cell death. Pathogenic tau species can propagate through synaptically connected networks and across the blood–brain barrier, contributing to widespread pathology. Increasing evidence implicates vascular dysfunction and endothelial cell senescence as mediators of tau-driven neurodegeneration. A deeper understanding of tau’s conformational transitions, intercellular transmission and interactions with glial and vascular elements has underpin global efforts to develop targeted therapies and biomarkers for early diagnosis and intervention.

Research from Nature Portfolio

Recent studies have demonstrated that soluble pathological tau aggregates are internalised by brain microvascular endothelial cells, inducing microtubule destabilisation, blockade of endothelial nitric oxide synthase (eNOS) activation and cellular senescence. Selective removal of these aggregates from a tauopathy model partially restores microvascular function and reduces neurodegenerative sequelae, highlighting a direct link between circulating tau species and vascular contribution to dementia. In addition, investigations into tau derived from Alzheimer’s disease brain have identified a rare phosphorylated high-molecular-weight form that is effectively taken up by neurons, transported along axons and transmitted to synaptically connected cells. This species, though low in abundance, appears to drive trans-synaptic propagation of tau pathology and represents a promising target for therapeutic intervention.

Tau Pathology in Neurodegenerative Disease Mechanisms publication trend

The graph below shows the total number of articles in tau pathology in neurodegenerative disease mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Tau oligomer: Small, soluble assemblies of tau protein that act as intermediate species in the aggregation pathway and exhibit potent neurotoxicity.

Hyperphosphorylation: Excessive addition of phosphate groups to tau, causing loss of microtubule affinity and promoting pathological aggregation.

High-molecular-weight tau: Tau assemblies with elevated molecular mass and phosphorylation, implicated in intercellular spread of pathology.

Endothelial nitric oxide synthase (eNOS): Enzyme in vascular endothelial cells that produces nitric oxide, crucial for maintaining vessel tone and health.

Cellular senescence: Irreversible arrest of cell division accompanied by a pro-inflammatory secretory phenotype and functional decline.

References

1. Roles of tau protein in health and disease. Acta Neuropathologica (2017).
2. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Molecular Neurodegeneration (2011).
3. Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy. Nature Communications (2023).
4. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nature Communications (2015).
5. A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology. Signal Transduction and Targeted Therapy (2024).
6. Common mouse models of tauopathy reflect early but not late human disease. Molecular Neurodegeneration (2023).