Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer's disease.

Overview

1. Department of Neuroscience, University of Virginia School of Medicine,Charlottesville, VA 22908 USA
2. Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine,Charlottesville, VA 22908 USA
3. Department of Psychology, University of Virginia,Charlottesville, VA 22904 USA
4. Neuroscience Graduate Program, University of Virginia,Charlottesville, VA USA

Abstract

The aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly correlated with the onset and progression of neurodegeneration in Alzheimer’s disease (AD). Increasing evidence implicates nuclear membrane disruption in AD and related tauopathies; however, whether this is a cause or consequence of neurodegeneration remains unresolved. Here, we show that nuclear lamina disruption emerges at the early Braak stages, coinciding with the initial formation of pathological tau aggregates in post-mortem AD brain tissue. Using the tauopathy mouse model (P301S PS19), we demonstrate that oligomeric tau (oTau) directly binds to the Lamin B Receptor (LBR), inducing nuclear envelope invaginations as revealed by electron microscopy. These structural alterations are accompanied by chromatin remodeling and gene expression dysregulation. To dissect the underlying mechanism, we employed a light-inducible OptoTau system (4R1N Tau::mCherry::Cry2Olig) in human iPSC-derived neurons, enabling real-time visualization of tau aggregation dynamics. This system revealed selective recruitment of oTau to the nuclear envelope and direct interactions with LBR and Lamin B2, leading to nuclear deformation and activation of the protein translational stress response. Together, these findings identify nuclear membrane disruption as an early and potentially causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization, nuclear stress, and chromatin remodeling. Targeting nuclear destabilization may offer new therapeutic avenues for mitigating AD pathogenesis.

Supplementary Information: The online version contains supplementary material available at 10.1007/s00401-026-03018-1.

Reproduced under the paper's license (CC BY), from the paper cited above.

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• doi:10.17632/ycb9n7gv8f.1, at the source; found in “Data and code availability”

Data and code availability

All data reported in this paper will be shared by the lead contact upon request. The raw IF, EM, DAB and WB images will be made publicly available at Mendeley Data (Reserved 10.17632/ycb9n7gv8f.1).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 6 keywords, 12 MeSH terms, 2 funders, 72 references, 2 RRIDs.

Cite

This paper

Yuan, S., Essepian, N., Roberts, R., Sherman, E., Wang, Q., Erisir, A., & Jiang, L. (2026). Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer's disease. Acta neuropathologica, 151(1), 43. https://doi.org/10.1007/s00401-026-03018-1

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