Anatabine lowers Alzheimer's A¦Â production in vitro and in vivo

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• 作者：Daniel  ; Paris ;   ; ^a ;   ; ^{dparis@rfdn.org} ; David  ; Beaulieu-Abdelahad^a ; Corbin  ; Bachmeier^a ; Jon  ; Reed^a ; Ghania  ; Ait-Ghezala^a ; Alex  ; Bishop^a ; Jin  ; Chao^a ; Venkat  ; Mathura^a ; Fiona  ; Crawford^a ; Michael  ; Mullan^a
• 关键词：Anatabine ; Alzheimer ; Amyloid ; Inflammation ; Secretase
• 刊名：European Journal of Pharmacology
• 出版年：2011
• 出版时间：30 November 2011
• 年：2011
• 卷：670
• 期：2-3
• 页码：384-391
• 全文大小：843 K

文摘

Brain A¦Â 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¦Â 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¦Â_1?0 and A¦Â_1?2 levels in a dose dependent manner and reduces sAPP¦Â production without impacting sAPP¦Á levels suggesting that anatabine lowers A¦Â production by mainly impacting the ¦Â-cleavage of APP. Additionally, we show that anatabine lowers NF¦ÊB activation at doses that inhibit A¦Â production in vitro. Since NF¦ÊB is known to regulate BACE-1 expression (the rate limiting enzyme responsible for A¦Â 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¦Â 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¦Â_1?0 and A¦Â_1?2 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¦Â accumulation.