The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1

Summary Background Neurofibrillary tangles formed from tau misfolding have long been considered one of the pathological hallmarks of Alzheimer's disease ( AD ). The misfolding of tau in AD correlates with the clinical progression of AD and inhibition or reversal of tau misfolding may protect the affected neurons. Methods We generated 293 and SH ‐ SY 5Y cells expressing DsRed‐tagged pro‐aggregation mutant of repeat domain of tau (ΔK280 tau RD ) to test indole/indolylquinoline derivatives for reducing tau misfolding and neuroprotection. Results Four of the 10 derivatives tested displayed good misfolding‐inhibitory effects on Tet‐On 293 cells. Among them, NC 009‐1 and NC 009‐7 enhanced heat‐shock 27 kDa protein 1 ( HSPB 1) expression to increase ∆K280 tau RD ‐DsRed solubility and promoted neurite outgrowth in Tet‐On SH ‐ SY 5Y cells. Knockdown of HSPB 1 resulted in decreased ∆K280 tau RD ‐DsRed solubility and reduced neurite outgrowth, which were rescued by addition of NC 009‐1/ NC 009‐7. Treatment with indole/indolylquinoline derivatives also improved neuronal cell viability and neurite outgrowth in mouse hippocampal primary culture under tau cytotoxicity. Conclusion Our results demonstrate how indole/indolylquinoline derivatives are likely to work in tau misfolding reduction, providing insight into the possible working mechanism of indole and indolylquinoline derivatives in AD treatment.