Anatabine lowers Alzheimer's Abeta production in vitro and in vivo.

摘要

Brain Abeta accumulation represents a key pathological hallmark in Alzheimer's disease. In this study, we investigated the impact of anatabine, a minor alkaloid present in plants of the Solanacea family on Abeta production in vitro using a cell line overexpressing the human amyloid precursor protein (APP) and in vivo using a transgenic mouse model of Alzheimer's disease. In vitro, anatabine lowers Abeta and Abeta levels in a dose dependent manner and reduces sAPPbeta production without impacting sAPPalpha levels suggesting that anatabine lowers Abeta production by mainly impacting the beta-cleavage of APP. Additionally, we show that anatabine lowers NFkappaB activation at doses that inhibit Abeta production in vitro. Since NFkappaB is known to regulate BACE-1 expression (the rate limiting enzyme responsible for Abeta production), we determined the impact of anatabine on BACE-1 transcription. We show that anatabine inhibits BACE-1 transcription and reduces BACE-1 protein levels in human neuronal like SHSY-5Y cells suggesting that the Abeta lowering properties of anatabine are mediated via a regulation of BACE-1 expression. In vivo, we show that an acute treatment with anatabine for four days significantly lowers brain soluble Abeta and Abeta levels in a transgenic mouse model of Alzheimer's disease. Altogether our data suggest that anatabine may represent an interesting compound for regulating brain Abeta accumulation.