Extracellular Tau Oligomers Rapidly Induce Nuclear Invagination in Neurons

Abstract

AbstractBackgroundNeuronal nuclei are normally spheroidal with a smoothly contoured surface. In Alzheimer’s disease (AD) and other tauopathies, however, neuronal nuclei often develop deep invaginations that include the nuclear lamina, a meshwork of intermediate filaments on the inner face of the inner nuclear membrane. The lamina is involved in numerous nuclear activities that might be adversely affected by invagination, including chromatin organization, nucleocytoplasmic trafficking of macromolecules, cell cycle regulation and apoptosis. Previous work showed that in vivo expression of pathogenically mutated human tau in Drosophila melanogaster neurons causes nuclear lamina invagination and that invaginated neuronal nuclei are found in human AD brain (Frost, et al. 2016. Current Biology 26; 129‐136). In light of this background we sought to shed further light on the mechanism of pathological nuclear invagination in mammalian neurons.MethodLamina invagination was assessed by immunofluorescence microscopy in human and mouse brain tissue, and in cultured mouse neurons using an antibody against lamin B1, a major subunit protein of the nuclear lamina. To ensure thorough neuroanatomical coverage in mouse brain, we stained lateral, medial, and middle sections from each brain, and imaged across the cortical region. To seek stimuli that would cause neuronal nuclear invagination, cultured mouse neurons were exposed to extracellular tau oligomers (xcTauOs).ResultWe detected nuclear invagination in neurons in brains of AD patients and CVN (APPSwDI;NOS2−/−) mice, in the latter of which nuclear invagination in cortical neurons was more frequent than in age‐matched wild type control neurons. In cultured mouse neurons, lamina invagination was induced by xcTauOs within one hour of exposure. This effect of xcTauOs was found to depend on intracellular tau, because nuclear invagination was not detected in neurons derived from tau knockout mice unless they expressed human tau by lentiviral transduction.ConclusionOur data confirm that nuclear invagination is common in both naturally occurring human AD and a transgenic mouse model of AD, and implicate xcTauOs as likely triggers of this phenomenon by a mechanism that also requires intracellular tau.