Background: Bexarotene, a retinoid X receptor agonist, has been shown to reverse neurodegeneration in mouse models of Alzheimer's disease (AD), accompanied by a decreased level of amyloid-β (Aβ), which is a hallmark of AD. However, the mechanism underlying this therapeutic effect may involve enhancing the sensitivity to insulin. Objective: This study was to test the hypothesis that bexarotene would protect against Aβ25-35-induced dysfunction through the insulin signaling pathway. Methods: Using a whole-cell patch clamp technique, the excitability and voltage-gated potassium currents of hippocampal neurons were examined in four groups of cells (control, Aβ, Aβ + bexarotene and bexarotene). Results: It was found that insulin increased the excitability of neurons. Bexarotene could enhance this effect and reverse the Aβ25-35-induced decrease in the firing rate of the action potential (AP). In addition, the properties of the single AP (sAP) and voltage-gated outward K+ currents were recorded, which finally showed similar changes to those in the firing frequency. Conclusion: The effects of bexarotene on Aβ-impaired excitability and sAP duration were mainly associated with K+ channels through insulin signaling pathway, which may be an additional mechanism underlying the protective effect of bexarotene on AD.

Keywords:
Alzheimer’s disease, Bexarotene, Excitability, Potassium currents, Insulin signaling pathway
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2014
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