Loss of AT8 Nuclear Tau as a Marker of Neuronal Ageing and Alzheimer’s Disease Progression

TL;DR

This study shows that a specific form of tau protein in neurons, called AT8, decreases with age and in Alzheimer’s disease, suggesting it could be an early marker of brain aging and disease progression.

Contribution

The novel finding is that nuclear AT8 tau is uniquely reduced in aging and Alzheimer’s disease, linking it to neuronal dysfunction and nuclear stress.

Findings

AT8 nuclear tau is abundant in young neurons but significantly reduced in aged and Alzheimer’s disease brains.

Loss of AT8 correlates with nucleolar disorganisation and neuronal cell cycle re-entry.

AT8 is the only nuclear tau epitope showing age- and disease-related changes.

Abstract

Background/Objectives: Tau protein, a central player in Alzheimer’s disease (AD) pathology, is classically known for its role in microtubule stabilisation. However, accumulating evidence indicates that tau also localises to the neuronal nucleus, particularly the nucleolus, where it may regulate chromatin organisation and transcription. In this study, we investigated whether different phosphorylation states of nuclear tau display age- and disease-dependent patterns, with a specific focus on the AT8 epitope (phospho-Ser202/Thr205). Methods: We analysed nuclear tau epitopes (Tau-1, AT8, PHF1, T181, and S262) by indirect immunofluorescence in SK-N-BE neuroblastoma cells under proliferative and retinoic acid-induced differentiated conditions and in post-mortem hippocampal CA1 neurons from foetal, young, aged, and AD brains. Other functional markers (UBTF, Ki67, fibrillarin and acetylated histone H4) were used to assess nuclear organisation and function. Results: Compared with the other epitopes, AT8 was unique in showing dynamic nuclear localisation: absent in proliferating cells but present after differentiation, abundant in young neurons, and significantly reduced in aged and AD samples. Nuclear AT8 co-localised with Ki67, and its decline was associated with neuronal cell cycle re-entry and nucleolar disorganisation. Conclusions: Among multiple nuclear tau epitopes, AT8 was the only one displaying age- and disease-related changes, and its reduction during ageing and AD correlates with nuclear stress, aberrant cell cycle activity, and neuronal vulnerability. Loss of nuclear AT8 may therefore represent an early marker of dysfunction in ageing and AD brains.

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