fig1

Figure 1. Overview of therapeutic mechanisms targeting neuronal tau production, aggregation, and propagation. (1) Antisense oligonucleotide (BIIB080) binding to MAPT mRNA can inhibit tau expression^[8,31-34]; (2) Inhibition of the GABAAR complex or GSK-3β genetic KO inhibits tau hyperphosphorylation^[22,35-40]; (3a) Genetic modification of low-density LRP1 to block lysine functional group and heparan sulfate competitive binding of HSPGs inhibit tau macropinocytosis^[41-45]; (3b) Tetrodotoxin blockade of Na⁺/K⁺ ATPase or AMPARs inhibits tau exocytosis from synaptic terminals^[46,47]; (4a) Myosin-10 blockers can inhibit nanotube formation, inhibiting tau intercellular spread^[48-51]; (4b) Drug GW4869 and nSMase2 silencing of ceramide inhibits exosomal synthesis, thus inhibiting tau intercellular spread^[52]; (5) CypD KO-driven inhibition of the VDAC1 pathway and sephin1/salubrinal inhibition of the ISR inhibit tau monomer hyperphosphorylation^[53,54]. MitoQ reduces ROS^[55,56]; (6) PARP1 KO inhibits tau hyperphosphorylation in the nucleus^[57]. Created with BioRender.com. AMPAR: AMPA receptors; ASO: antisense oligonucleotide; CReP: constitutive repressor of eIF2α phosphorylation; CypD: cyclophilin D; GABAAR: γ-aminobutyric acid sub-type A receptor; GADD34: growth arrest and DNA damage-inducible protein 34; GSK-3β: glycogen synthase kinase-3β; HSPGs: heparan sulfate proteoglycans; ISR: integrated stress response; KO: knockout; LRP1: lipoprotein receptor-related protein 1; MAPT: microtubule-associated protein tau; PARP1: poly (ADP-ribose) polymerase-1; ROS: reactive oxidative species; TTX: tetrodotoxin; VDAC1: voltage-dependent anion channel protein 1.