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

INTRODUCTION: Neuronal nuclei are normally smoothly surfaced. In Alzheimer’s disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies. METHODS: Nuclear invagination was assayed by immunofluorescence in brain, and in cultured neurons before and after extracellular tau oligomers (xcTauO) exposure. Nucleocytoplasmic transport was assayed in cultured neurons. Gene expression was investigated using nanoString nCounter technology and qRT-PCR. RESULTS: Invaginated nuclei were twice as abundant in human AD as in cognitively normal adults, and were increased in mouse neurodegeneration models. In cultured neurons, nuclear invagination was induced by xcTauOs by an intracellular tau-dependent mechanism. xcTauOs impaired nucleocytoplasmic transport, increased histone H3 trimethylation at lysine 9 and altered gene expression, especially by increasing tau mRNA. DISCUSSION: xcTauOs may be a primary cause of nuclear invagination in vivo, and by extension, impair nucleocytoplasmic transport and induce pathogenic gene expression changes.