DpdtpA, A Multi-metal Ion Chelator, Attenuates Tau Phosphorylation and Microglial Inflammatory Response via Regulating the PI3K/AKT/GSK-36 Signal Pathways

Tau protein hyperphosphorylation and formation of intracellular neurofibrillary tangles (NFTs) are one of the histopathological hallmarks of Alzheimer's disease (AD) and positively correlated with the severity of AD symptoms. NFTs contain a large number of metal ions that play an important role in regulating tau protein phosphorylation and AD progression. Extracellular tau induces primary phagocytosis of stressed neurons and neuronal loss by activating microglia. Here, we studied the effects of a multi-metal ion chelator, DpdtpA, on tauinduced microglial activation and inflammatory responses and the underlying mechanisms. Treatment with DpdtpA attenuated the increase in the expression of NF-xB and production of inflammatory cytokines, IL-16, IL-6 and IL-10, in rat microglial cells induced by expression of human tau40 proteins. Treatment with DpdtpA also suppressed tau protein expression and phosphorylation. Moreover, treatment with DpdtpA prevented tauinduced activation of glycogen synthase kinase-36 (GSK-36) and inhibition of phosphatidylinositol-3-hydroxy kinase (PI3K)/AKT. Collectively, these results show that DpdtpA can attenuate tau phosphorylation and inflammatory responses of microglia by regulating the PI3K/AKT/GSK-36 signal pathways, providing a new option to alleviate neuroinflammation for the treatment of AD.& COPY; 2023 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

Tau protein hyperphosphorylation and NFTs formation are key features of AD, and DpdtpA can attenuate these processes by regulating the PI3K/AKT/GSK-36 signaling pathway. DpdtpA also reduces microglial activation and inflammatory responses induced by Tau, offering a potential treatment option for AD-associated neuroinflammation.