Anatabine lowers Alzheimer's Aβ production in vitro and in vivo

Brain A beta 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 A beta 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 A beta(1-40) and A beta(1-42) levels in a dose dependent manner and reduces sAPP beta production without impacting sAPP alpha levels suggesting that anatabine lowers A beta production by mainly impacting the beta-cleavage of APP. Additionally, we show that anatabine lowers NF kappa B activation at doses that inhibit A beta production in vitro. Since NF kappa B is known to regulate BACE-1 expression (the rate limiting enzyme responsible for A beta 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 A beta 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 A beta(1-40) and A beta(1-42) levels in a transgenic mouse model of Alzheimer's disease. Altogether our data suggest that anatabine may represent an interesting compound for regulating brain A beta accumulation. (C) 2011 Elsevier B.V. All rights reserved.