Neurotraffic: oriented neuronal networks for investigating the mechanisms of tau propagation

Abstract

Neurofibrillary tangles (NFTs), a pathological hallmark of Alzheimer’s disease (AD), consist of insoluble aggregates of hyperphosphorylated tau protein. In AD, NFTs are seen to accumulate first in the entorhinal cortex, and with progression of AD they appear in neighbouring regions such as the hippocampus, followed by the neocortex in late stages. Examination of the neuroanatomical localisation of NFTs in AD brains suggests that the NFTs spread through the brain due to the propagation of pathogenic tau along anterograde connected brain circuits.

Pathogenic tau can spread between cells, and it can act as a prion-like seed, inducing misfolding of healthy tau. However, it is not yet known how tau spreads between neurons, or if the diseased cells need to die in order to propagate pathology. In this project, we recreated a minimalistic neuronal circuit, and established a robust and reproducible system through which tau propagation can be examined extensively in vitro. With this we show that pathogenic tau formed in a diseased donor neuron can both spread intracellularly, and trigger a prion-like misfolding of healthy tau in connected neurons, without the death of the do neurons. We determined that pathogenic tau is actively spread along intact neuronal circuits, with a preference for anterograde directionality. We also discovered tau aggregation-resistance in a neuronal subpopulation, and in an axonal subcompartment.

Our established method of interrogating the propagation of tau in disease can now be used for further studies to determine the specific molecular mechanisms at play.

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Identifiers

ORCID for Katrin Deinhardt: orcid.org/0000-0002-6473-5298

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