Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers

Oligomeric and filamentous tau are key pathogenic factors in tauopathies, such as Alzheimer’s Disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). Tauopathy spreads from neuron to neuron by cycles of tau aggregate release into the extracellular space and subsequent neuronal uptake. While the mechanisms of this prion-like spread of pathogenic tau have been extensively studied, the cell biological responses of neurons to aggregated tau uptake have attracted much less attention.
The nuclear lamina, a meshwork of intermediate filaments underlying the inner nuclear membrane, plays critical roles in the maintenance of normal nuclear structure and function. Deformation of the nuclear membrane, including nuclear lamina invagination, has been implicated in multiple neurodegenerative diseases, including AD, FTD, and Parkinson’s disease, and can be provoked by dysfunctional tau. With this background in mind, we investigated whether extracellular tau oligomers (xcTauOs) affect neuronal nuclei. We demonstrate that xcTauOs rapidly cause striking nuclear invagination by a mechanism that depends on intracellular tau, and is associated with disrupted nucleocytoplasmic transport, and altered chromatin structure and gene transcription. Altogether, our results implicate xcTauOs as seminal factors in the conversion of healthy neurons into diseased neurons in AD and other tauopathies.