JWX-A0108, a positive allosteric modulator of α7 nAChR, attenuates cognitive deficits in APP/PS1 mice by suppressing NF-κB-mediated inflammation

Abstract

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer’s disease (AD). Studies have shown that cholinergic lesion is a contributor for the pathophysiology of AD. The α7 nicotinic acetylcholine receptors (nAChRs), a subtype of nAChRs, are abundantly expressed in the brain regions related to cognition and memory, such as hippocampus and frontal cortex. The α7 nAChR is rapidly activated and desensitized by agonists. JWX-A0108 is a type I positive allosteric modulator (PAM) of α7 nAChR, which mainly enhances agonist-evoked peak currents. Here, we used the Morris Water Maze to evaluate the effect of JWX-A0108 on cognition and memory functions in APP/PS1 mice, and the mechanism related to anti-inflammatory effect. The results showed that JWX-A0108 could improve the learning and memory function of APP/PS1 transgenic mice in Morris water maze, decrease the expression of IL-1β, TNF-α, IL-6 in the brain and lower the phosphorylation level of IκBα (Ser32/36) and NF-κB p65 (Ser536), decrease the expression of Iba1, the microglia activation marker. Nissl staining showed that the CA3 and DG regions of hippocampus were damaged in APP/PS1 mice, which was improved by JWX-A0108. All of these effects of JWX-A0108 were reversed by MLA (α7 nAChR specific blocker). Taken together, the results reveal that JWX-A0108 improved the learning and memory function of APP/PS1 mice by enhancing the anti-inflammatory effect of the endogenous choline system through α7 nAChR, inhibited the activation of the NF-κB signaling pathway by inhibiting IκB phosphorylation, and ultimately inhibited inflammatory responses.