Table 2.

A summary of recent tau transmission models.

Forms of Tau	Animal/Cell Model	Conformation/Characteristics	‘Prion-Like’ Transmission	Reference
2N4R tau monomer	Mouse primary hippocampal and cortical neurons Non-neuronal cells including HEK293, Hela, MC17, and MLECs	Wild-type tau-paperclip like	Internalized by non-neuronal cells, MLECs 3-O-sulfation is required for HSPG-mediated tau monomer internalization	[41,42]
2N4R tau oligomers		Spherical structure Diameters ranging from 10 nm to 30 nm	Dynamin-dependent endocytosis Bulk endocytosis Tau species in endosome transported in neurons anterogradely and retrogradely
Heparin-induced tau short fibrils (2N4R)		Helical twist Varied length, from 40 nm to 250 nm
Tau filaments purified from rTg4510 mouse brain	Primary neurons Hela cells P301L tau expressing mice	Fibrillary structure	Internalized by neuronal cells, but not non-neuronal cells 1-week post-injection, NFTs were detected by immunostaining against MC1at the tau aggregates injection site
Heparin-induced tau long fibrils (2N4R)	Primary neurons Hela cells	Helical twist Varied length, from 200 nm to 1600 nm	No internalization detected in both neuronal cells and non-neuronal cells
2N4R tau monomer	Human neuroglioma, H4 cells Human SH-SY5Y hiPSC-derived neurons	Size averaged at 5.7 nm	Internalized by neuronal cells rapidly HSPG-dependent internalization Tau monomer interacts with 6-O-sulfation on the HSPGs, but not N-sulfation	[36]
Heparin-induced oligomer (2N4R)		Helical filaments/19 nm
Short fibrils (2N4R)		Helical fragments/33nm
Heparin-induced fibrils (2N4R)		Helical filaments/80 nm	Less internalization detected in both cell lines
Tau RD monomers	Mouse NPCs, C17.2 Primary neurons	Wild-type tau repeat domain	No internalization detected	[8,40]
Heparin-induced tau fibrils (both RD and WT 2N4R)		Fibrillary structure	Tau fibrils require HSPGs for neurons 6-O- and N-sulfation are required for tau aggregates internalization HSPG mediated intracellular tau seeding Actin-dependent macropinocytosis Clathrin- or dynamin-independent endocytosis
Tau P301S monomer	hiPSCs-derived cortical neurons	Seeding-prone form	Actin-dependent macropinocytosis Dynamin-dependent endocytosis	[35]
Heparin-induced tau fibrils (Tau P301S)		Fibrillary structure	Dynamin-dependent endocytosis Actin-independent endocytosis
Tau oligomers	Mouse primary neuronal cells HEK293 CHO cells	Spherical structure	Muscarinic receptor-mediated endocytosis of tau by neuronal and HEK293 cells, but not by CHO cells Muscarinic receptor highly expressed by neuronal cells	[43]
Soluble tau oligomers derived from AD patient	Mouse primary neuronal cells	Spherical structure	Muscarinic receptor-mediated endocytosis of tau
2N4R tau monomer, oligomers, and fibrils	H4 neuroglioma hiPSCs-derived neuronal cells	Spherical structure Filaments	Receptor-mediated tau endocytosis Knockdown of LRP1 blocks soluble tau uptake including tau monomers/oligomers, but only reduce tau fibrils uptake	[36]