Abstract
Most neurodegenerative disorders are associated with aggregation and accumulation of misfolded proteins. One of these proteins, tau, is involved in a number of pathologies including Alzheimer's disease and frontotemporal dementia. Aggregation and phosphorylation of tau have been shown to be a trigger for abnormal signal transduction and disruption of cellular homeostasis. Here, we have studied the effect of extracellular tau at different stages of aggregation in cortical co-cultures of neurons and astrocytes, to understand how this process affects tau pathogenicity. We found that the species formed after prolonged invitro aggregation of tau (longer than 1day) are able to stimulate reactive oxygen species (ROS) production through the activation of NADPH oxidase without decreasing the level of the endogenous antioxidant glutathione. The same late insoluble aggregates of tau induced calcium signals in neurons and a gradual increase in the ionic current of artificial membranes. Both tau-induced calcium signals and ROS production in NADPH oxidase were reduced in the presence of the inhibitor of voltage-gated calcium channels (VGCC) nifedipine. This suggests that insoluble aggregates of tau incorporate into the membrane and modify ionic currents, changing plasma membrane potential and activating VGCCs, which induces a calcium influx that triggers ROS production in NADPH oxidase. The combination of all these effects likely leads to toxicity, as only the same insoluble tau aggregates which demonstrated membrane-active properties produced neuronal cell death.
Highlights
Despite the difference in aetiology and in the mechanisms of pathology, most neurodegenerative disorders have similar features such as the accumulation of abnormally aggregated proteins and the involvement of mitochondria and oxidative stress in the pathogenesis.In Alzheimer’s disease (AD), the protein tau becomes abnormally clumped to form ‘tangles’
We first investigated if the exposure of co-cultures of primary neurons and astrocytes to the different tau aggregates had a toxic effect, and if changes in the aggregation status of tau are able to induce neuronal death
We show that in addition, extracellular tau aggregates exert a direct pathogenic effect in neuronal–astrocytic cultures, and, more importantly, these effects directly depend on the stage of tau aggregation
Summary
Despite the difference in aetiology and in the mechanisms of pathology, most neurodegenerative disorders have similar features such as the accumulation of abnormally aggregated proteins and the involvement of mitochondria and oxidative stress in the pathogenesis. In Alzheimer’s disease (AD), the protein tau becomes abnormally clumped to form ‘tangles’. This clumping process is highly dynamic, and during it, a number of intermediates are formed which differ in size, structure and morphology. Abnormal deposition of aggregates of the protein tau is involved in a Abbreviations. The FEBS Journal (2020) a 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of
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