title: Anatabine lowers Alzheimer's Aβ production in vitro and in vivo.
abstract: Brain Aβ 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 Aβ 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 Aβ₁₋₄₀ and Aβ₁₋₄₂ levels in a dose dependent manner and reduces sAPPβ production without impacting sAPPα levels suggesting that anatabine lowers Aβ production by mainly impacting the β-cleavage of APP. Additionally, we show that anatabine lowers NFκB activation at doses that inhibit Aβ production in vitro. Since NFκB is known to regulate BACE-1 expression (the rate limiting enzyme responsible for Aβ 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 Aβ 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 Aβ₁₋₄₀ and Aβ₁₋₄₂ levels in a transgenic mouse model of Alzheimer's disease. Altogether our data suggest that anatabine may represent an interesting compound for regulating brain Aβ accumulation.
authors.affiliation: Roskamp Institute, 2040 Whitﬁeld Avenue, Sarasota, FL 34243, USA. dparis@rfdn.org
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
authors.forename: David
authors.initials: D
authors.lastname: Beaulieu-Abdelahad
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.forename: Jon
authors.initials: J
authors.lastname: Reed
authors.forename: Ghania
authors.initials: G
authors.lastname: Ait-Ghezala
authors.forename: Alex
authors.initials: A
authors.lastname: Bishop
authors.forename: Jin
authors.initials: J
authors.lastname: Chao
authors.forename: Venkat
authors.initials: V
authors.lastname: Mathura
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000097:blood / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D011725:Pyridines; C012737:anatabine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human