Neuronal intracellular aggregates, containing misfolded tau protein, are observed in individuals with Alzheimer's disease. As neurodegeneration progresses, tau aggregates appear sequentially in distinct brain regions, in a pattern which is predictable and consistent between individuals. It has been proposed that aggregated tau actively spreads from diseased to healthy neurons.

Using stem cell-derived human cortical neurons, we have studied uptake of different forms of tau. Neuronal internalisation of tau has been assessed by flow cytometry, and live imaging analysis on the Opera Phenix platform.

Monomeric and aggregated tau enter neurons by different vesicular pathways. Internalised tau co-localises with endosomal and lysosomal markers and these vesicles can be seen to be trafficked along neurites. Chemical inhibition of pathways involved in endocytosis has shown that monomeric and aggregated forms of tau primarily enter neurons via different processes; suggesting that transfer of tau between neurons is a constitutive biological process and not disease-specific. This assay provides the basis for a live-imaging based screen to identify modifiers of entry and proteostasis of toxic forms of tau, to prevent the spread of neurodegeneration.