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

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) brain, 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 neuron 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 used to inject into the lateral ventricle, and the Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. 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 here found that IL-17 was increased in APP/PS1 mice, and it induced neural damage by the 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 C57BL/6 mice by downregulation 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 downregulation of the TRAF6/NF-κB pathway, which provides new clues for the mechanism of Aβ-induced cognitive impairments, and a basis for therapeutic intervention.