TABLE 5.

Approaches to enhance tau degradation by AELN.

Category	Name of interventions	Affected pathways	Mechanism of action	Models tested	Clinical trials	References
Cathepsin inhibitors	EA-1	Lysosomes, tau cleavage, potentially CMA	Inhibits cathepsin D, which is involved in the lysosomal dysfunction and notably in the cleavage of the tau protein into tangle-like fragments	Organotypic hippocampal slice cultures	N/A	Bi et al., 2002
Chaperone modulators	VER-155008	CMA	Hsc70 inhibitor, reduces PHF-tau, reverses axonal degeneration, recovers memory function. Possibly inhibiting CMA and activating other tau degrading pathways	5XFAD mice	N/A	Yang and Tohda, 2018
Autophagy inducers	Lithium	Autophagy	Induces autophagy and inhibits GSK-3β-mediated tau phosphorylation	P301L Tau mice	Currently in AD Phase II clinical trial, NCT02129348	Shimada et al., 2012
Autophagy inducers	Trehalose	Autophagy	mTOR-independent autophagy inducer, activates AMPK and clears mutant tau	Primary neurons, P301S MAPT transgenic mouse	N/A	Schaeffer and Goedert, 2012
Autophagy inducers	Cilostazol	Autophagy	Upregulates Beclin 1, ATG5, LC3, and lysosomal Cathepsin B and downregulates mTORC1 and p300, and reduced tau acetylation and phosphorylation	N2a cells	Clinically approved for vascular disease, currently in AD Phase II clinical trial, NCT02491268	Lee et al., 2014
Autophagy inducers	Methylene blue	Autophagy	Inhibits tau oligomerization and promotes autophagy	Organotypic hippocampal slice/neurons and JNPL3 transgenic mouse with human P301L tau	Finished four Phase III clinical trials: NCT01689246 NCT01689233 NCT01626378 NCT02245568 Ongoing: NCT02380573	Congdon et al., 2012; Gauthier et al., 2016; Wilcock et al., 2018; Schelter et al., 2019; Shiells et al., 2020
Autophagy inducers	Temsirolimus	Autophagy	Reduced the accumulation of phosphorylated tau	SH-SY5Y cells and P301S tauopathy mice	N/A	Jiang et al., 2014
Tyrosine-protein kinase ABL1 inhibitor	Nilotinib	Autophagy	Inhibits autophagy negative regulator ABL1 and induces neuroprotective autophagy to reduce tau and improve astrocytic function	P301L Tau mice	Currently in AD Phase II clinical trial, NCT02947893	Hebron et al., 2018
Farnesyltrans ferase inhibitor	Lonafarnib	Autophagy	Farnesyltransferase inhibition prevents Rhes-mediated tau accumulation and activates autophagy	rTg4510, AD patient-derived human iPSC-differentiated neurons	Already in use in human patients for treating cancer	Hernandez et al., 2019
TFEB activators	Curcumin Analog C1	Activation of TFEB and autophagy-lysosomal pathways	Reduced the accumulation of phosphorylated tau	Mouse and rat primary neurons, 5xFAD, P301S, and 3xTg-AD mice	Multiple trials completed or currently in AD Phase II clinical trials	Song et al., 2020
TFEB activators	Flavonol Fisetin	Activation of TFEB, autophagy-lysosomal pathways	Induced activation of TFEB and autophagic degradation of phosphorylated tau	293T cells co-transfected with plasmids expressing tau and constitutively active HA-GSK-3β-S9A	Currently in AD Phase II clinical trial, NCT02380573	Currais et al., 2014
TFEB activators	Flubendazole	Activation of TFEB, autophagy-lysosomal pathways	Reduced the accumulation of phosphorylated tau	N2a cells	N/A	Chauhan et al., 2015
TFEB activators	Bromhexine	Activation of TFEB, autophagy-lysosomal pathways	Reduced the accumulation of phosphorylated tau	N2a cells	N/A	Chauhan et al., 2015
TFEB activators	Optogenetics	Activation of TFEB, autophagy-lysosomal pathways	Reduced the accumulation of phosphorylated tau	N2a cells, AD patient-derived human iPSC-differentiated neurons	N/A	Binder et al., 2020
Tau antibodies	Various antibodies	Lysosomal degradative pathways	Reduce oligomerization of tau and enhance tau degradation through AELN inside neurons or microglia	Various transgenic mice	Currently in Phase I or II AD clinical trials	Congdon and Sigurdsson, 2018