Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways

Evans LD et al (2018) Cell Reports 22(13): 3612–3624. DOI: 10.1016/j.celrep.2018.03.021

Highlights from the paper

• Extracellular tau protein enters human neurons by endocytosis and micropinocytosis
• Aggregated tau enters human neurons primarily by endocytosis
• Tau antibodies reduce uptake and are carried into neurons by tau
• Findings suggest that tau uptake is dependent on carrier proteins or receptors

 Summary from the paper

In Alzheimer’s disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process.

We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons.

These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon.

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