Activation of the IL-17/TRAF6/NF-κB pathway is implicated in Aβ-induced neurotoxicity

Abstract

Abstract Background Neuroinflammation plays a critical role in amyloid-β (Aβ) pathophysiology. The cytokine interleukin-17A (IL-17) is involved in the learning and memory process in the central nervous system, and its level was reported to be increased in Alzheimer's disease (AD) brains, while the effect of IL-17 on the course of Aβ has not been well defined. Methods Here, we used APP/PS1 mice to detect the IL-17 expression level. Primary hippocampal neurons were treated with IL-17, and immunofluorescence was used to investigate whether IL-17 induced neuronal damage. At the same time, male C57BL/6 mice were injected with Aβ42 to mimic the Aβ model. Then, IL-17 neutralizing antibody (IL-17Ab) was injected into the lateral ventricle, and the open-field test, novel objective recognition test, and fear conditioning test were used to detect cognitive function. Long-term potentiation (LTP) was used to assess synaptic plasticity, molecular biology technology was used to assess the IL-17/TRAF6/NF-κB pathway, and ELISA was used to detect inflammatory factors. Results Altogether, we found that IL-17 was increased in APP/PS1 mice and induced neural damage by administration to primary hippocampal neurons. Interestingly, using Aβ42 mice, the results showed that the level of IL-17 was increased in Aβ42 model mice, and IL-17Ab could ameliorate Aβ-induced neurotoxicity and cognitive decline in 10 C57BL/6 mice by downregulating the TRAF6/NF-κB pathway. Conclusion These findings highlight the pathogenic role of IL-17 in Aβ-induced synaptic dysfunction and cognitive deficits. Inhibition of IL-17 could ameliorate Aβ-induced neurotoxicity and cognitive decline in C57BL/6 mice by downregulating the TRAF6/NF-κB pathway, which provides new clues for the mechanism of Aβ-induced cognitive impairments.

Keywords

• IL-17
• Aβ
• IL-17Ab
• Synaptic dysfunction
• Cognitive decline