Knockin’ on heaven’s door: Molecular mechanisms of neuronal tau uptake

Since aggregates of the microtubule‐binding protein tau were found to be the main component of neurofibrillary tangles more than 30 years ago, their contribution to neurodegeneration in Alzheimer's disease (AD) and tauopathies has become well established. Recent work shows that both tau load and its distribution in the brain of AD patients correlate with cognitive decline more closely compared to amyloid plaque deposition. In addition, the amyloid cascade hypothesis has been recently challenged because of disappointing results of clinical trials designed to treat AD by reducing beta‐amyloid levels, thus fuelling a renewed interest in tau. There is now robust evidence to indicate that tau pathology can spread within the central nervous system via a prion‐like mechanism following a stereotypical pattern, which can be explained by the trans‐synaptic inter‐neuronal transfer of pathological tau. In the receiving neuron, tau has been shown to take multiple routes of internalisation, which are partially dependent on its conformation and aggregation status. Here, we review the emerging mechanisms proposed for the uptake of extracellular tau in neurons and the requirements for the propagation of its pathological conformers, addressing how they gain access to physiological tau monomers in the cytosol. Furthermore, we highlight some of the key mechanistic gaps of the field, which urgently need to be addressed to expand our understanding of tau propagation and lead to the identification of new therapeutic strategies for tauopathies. [Image: see text]