Lulu Jiang, MD, PhD
Research from the lab of Lulu Jiang, MD, PhD, in the Department of Neuroscience and the Center for Brain Immunology and Glia at the University of Virginia School of Medicine, has identified a previously unrecognized early mechanism of neurodegeneration in Alzheimer’s disease (AD), showing that tau oligomerization directly drives nuclear membrane deformation and chromatin remodeling. The findings were published in Acta Neuropathologica, a leading peer-reviewed journal in neuropathology.
“The study demonstrates that aggregation of the microtubule-associated protein tau into oligomeric complexes is strongly associated with disease onset and progression in AD,” said Dr. Jiang, assistant professor in the Department of Neuroscience and senior author of the study. “While nuclear membrane disruption has been increasingly implicated in neurodegenerative disease, its temporal relationship to tau pathology has remained unclear.”
Using post-mortem human brain tissue, the researchers found that nuclear lamina disruption emerges at early Braak stages, coinciding with the initial formation of pathological tau aggregates. These findings suggest that nuclear structural alterations occur at a very early phase of disease progression.
In a tauopathy mouse model, the team, in collaboration with the lab of Alev Erisir, MD, PhD, in the UVA Department of Psychology, showed that oligomeric tau (oTau) directly binds to the Lamin B Receptor (LBR), a critical component of the nuclear envelope. This interaction induces pronounced nuclear envelope invaginations, as revealed by electron microscopy, and is accompanied by widespread chromatin remodeling and gene expression dysregulation.
To further define the underlying mechanism, the researchers employed a light-inducible optogenetic tau aggregation system in human iPSC-derived neurons. This system enabled real-time visualization of tau aggregation dynamics and revealed selective recruitment of oligomeric tau to the nuclear envelope. At this site, tau interacts with both LBR and Lamin B2, leading to nuclear deformation and activation of a translational stress response.
“These findings establish a direct mechanistic link between tau oligomerization and nuclear structural failure,” stated Dr. Jiang. “Importantly, they suggest that nuclear membrane disruption is not merely a downstream consequence of neurodegeneration, but may be an early and potentially causative event in Alzheimer’s disease.”
Together, these results identify nuclear membrane destabilization as a central event in tau-mediated neurodegeneration, linking tau aggregation, nuclear stress, and chromatin remodeling. The researchers propose that targeting nuclear envelope integrity may offer a novel therapeutic strategy for slowing or preventing Alzheimer’s disease progression.
Findings Published
Yuan S, Essepian N, Roberts R, Sherman E, Wang Q, Erisir A, Jiang L. Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer’s disease. Acta Neuropathologica. 2026;151:43. https://link.springer.com/article/10.1007/s00401-026-03018-1
Filed Under: Research