Table 1.

Summary of main studies supporting different pathways involved in tau secretion.

Secretory pathway		In vitro	In vivo	Type of tau	Secreted tau	References
Unconventional protein secretion type I/Translocation through the plasma membrane		Cell lines (Neuro2A, SH-SY5Y, CHO, and HEK293), mouse and rat primary neurons		Wt human tau (0N4R, 2N4R) and E14, endogenous murine tau	Full-length and truncated forms, phosphorylated, mostly small soluble oligomers	Chai et al. (2012), Katsinelos et al. (2018), and Merezhko et al. (2018)
Membranous organelles-based secretion	Exosomal secretion	Cell lines (HEK293, COS7, N2A, and M1C), rat primary neurons	Mouse brain, human CSF	Wt human tau (3R, 0N4R, 1N4R), P301S, 4R domain of human tau ΔK280, endogenous rat tau, and endogenous human tau	Full-length and truncated forms, hypophosphorylated, monomeric and oligomeric, partly insoluble	Saman et al. (2012), Simón et al. (2012), Asai et al. (2015), and Wang et al. (2017)
	Autophagy-based secretion	Cell lines (SH-SY5Y and HEK293), murine primary neurons, human iPSC-derived neurons		Wt human tau (all 6 isoforms), endogenous rat tau, endogenous human tau	Full-length and truncated forms	Tang et al. (2015), Lonati et al. (2018), Kang et al. (2019), and Chen et al. (2020)
	LE/lysosomal secretion	Cell lines (HEK293, M17, and HeLa), rat primary neurons, mouse organotypic brain slices		Wt tau (0N4R and 1N4R), R406W, P301L, and endogenous murine tau	Truncated forms, hypophosphorylated	Fontaine et al. (2016), Rodriguez et al. (2017), and Xu Y. et al. (2018)
Ectosomal secretion		Cell line (N1-E115), rat primary neurons	Rat ISF, human CSF	Wt human tau (1N4R), endogenous rat tau, endogenous human tau	Full-length, C- and N-terminal truncated forms	Dujardin et al. (2014) and Spitzer et al. (2019)

E14, a pseudo hyperphosphorylated form of tau; wt, wild type; CSF, cerebrospinal fluid; iPSC, induced pluripotent stem cell; ISF, interstitial fluid.