Anti-Malarial Drug Artemisinin Extenuates Amyloidogenesis and Neuroinflammation in APPswe/PS1dE9 Transgenic Mice Via Inhibition of NF-κB and NLRP3 Inflammasome Activation (IN9-2.004)

Abstract

OBJECTIVE: To test if artemisinin, an anti-Malarial drug, can slow down the amyloidogenesis and neuroinflammation in APPswe/PS1dE9 transgenic mice and the mechamism will be investigated further.

BACKGROUND: Neuroinflammation is thought to be the key mechanism linked to Alzheimer's disease (AD) pathogenesis, which is deeply invovled in amyloid plaques, neurofibrillary tangles and microglia activation. Artemisinin has been reported to exert anti-inflammatory effects but the exact machanism need to clarified, and the effect of downregulation of amyloid deposition indicates the new direction for AD secondary prevention strategies.

DESIGN/METHODS: 5-month-old APPswe/PS1dE9 transgenic mice were used to evaluate the effects of artemisinin on AD pathogenesis, Five mice were injected with 40 mg/kg artemisinin in DMSO at the same time once daily, for continuous 30 days. The other five mice were injected with DMSO as control. Immunohistochemical staining, Western Blotting, ELISA were combined to evaluate the expression or levels of soluble and insoluble Aβ42, IL-6, TNF-α, IL-1β,LRP1, RAGE, APP carboxyl terminal, BACE1, PS1, Aph-1a, serine 536 phosphorylated NF-κB p65, NF-κB p65, IκB-α, serine 32 phosphorylated IκB-α, NALP3, Cleaved Caspase-1 (Asp297).

RESULTS: We found that artemisinin treatment can (1) decreased neuritic plaque burden; (2) didn't alter Aβ transport across the blood–brain barrier; (3) regulated APP processing via inhibiting β-secretase activity; (4) inhibited NF-κB activity and NALP3 inflammasome activation in APPswe/PS1dE9 double transgenic mice. The in vivo study clearly demonstrates that artemisinin has protective effects on AD pathlogy due to its effects on suppressing NF-κB activity and NALP3 inflammasome activation.

CONCLUSIONS: The in vivo study clearly demonstrates that artemisinin has protective effects on AD pathlogy due to its effects on suppressing NF-κB activity and NALP3 inflammasome activation. Furthermore, Our study suggests that artemisinin could be potent candidate in the secondary prevention drugs for AD.

Supported by: National Natural Science Foundation of China grant (30700248; 81271211), and Jiangsu Provincial Natural Science Foundation of Basic Research Plan (BK2009049). We thank Laboratory Animal Center of Nanjing First Hospital for breeding the animals and providing animal experimental facility.

Disclosure: Dr. Shi has nothing to disclose. Dr. Xu has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Sun has nothing to disclose.