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A number of neurodegenerative disorders including Alzheimer’s disease, progressive supranuclear palsy (PSP) and some forms of frontotemporal dementia (FTD) are associated with the build-up of abnormal tau proteins inside neurons. In the healthy brain, tau is located mainly in axons, but in tauopathies the protein becomes hyperphosphorylated and accumulates in the form of intraneuronal aggregates called neurofibrillary tangles. Tangles are associated with neuronal loss and cognitive impairment in patients, but there is also increasing evidence that tangles may not be acutely toxic and can persist inside intact neurons for at least several months. For example, previous results obtained in the rTg4510 mouse model of tauopathy revealed that tangle-bearing neurons respond to novel environments with immediate early gene expression, while in the primary visual cortex tangle-bearing neurons show normal responses to visual stimuli (see Spires-Jones and Hyman, 2014). On the other hand, tangles have been shown to be associated with more subtle neuronal impairments including synapse loss and reduced levels of synaptic vesicle proteins, as well as alterations in the axon initial segment, impaired nucleocytoplasmic transport, and clustering of mitochondria in the soma (Polanco et al., 2018). Assessing the toxicity of tangles is not straightforward and the impact of tangles on neuronal function remains a highly debated yet fundamental question in the field. In this issue of Brain, Marinković and co-workers use longitudinal imaging with in vivo multiphoton microscopy in a model of cortical tangle formation (mutant human tau-overexpressing P301S mice injected with synthetic tau fibrils) to compare the functional properties of tangle-containing versus tangle-free neurons and to track the natural history of these cells (Marinković et al., 2019). This is a powerful experimental approach that makes it possible to visualize directly and with high resolution the longterm functional consequences of newly formed tangles in individual neurons in the living brain (Fig. 1A).

Tau suppresses neuronal activity in vivo, even before tangles form