title: Depletion of CXCR2 inhibits γ-secretase activity and amyloid-β production in a murine model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive decline. Recent studies from our group and others have suggested that certain G-protein coupled receptors (GPCRs) can influence the processing of the amyloid precursor protein (APP). Earlier, we demonstrated that stimulation of a chemokine receptor, CXCR2, results in enhanced γ-secretase activity and in increased amyloid-beta (Aβ) production. Taken together, results obtained from in vitro studies indicate that therapeutic targeting of CXCR2 might aid in lowering Aβ levels in the AD brain. To better understand the precise function and to predict the consequences of CXCR2 depletion in the AD brain, we have crossed CXCR2 knockout mice with mice expressing presenilin (PS1 M146L) and APPsw mutations (PSAPP). Our present study confirms that CXCR2 depletion results in reduction of Aβ with concurrent increases of γ-secretase substrates. At the mechanistic level, the effect of CXCR2 on γ-secretase was not found to occur via their direct interaction. Furthermore, we provide evidence that Aβ promotes endocytosis of CXCR2 via increasing levels of CXCR2 ligands. In conclusion, our current study confirms the regulatory role of CXCR2 in APP processing, and poses it as a potential target for developing novel therapeutics for intervention in AD.
authors.affiliation: Laboratories of Chemical Biology and Drug Discovery in Neurology, Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, United States. Pbakshi@rfdn.org
authors.forename: Pancham
authors.initials: P
authors.lastname: Bakshi
authors.forename: Elaina
authors.initials: E
authors.lastname: Margenthaler
authors.forename: Jon
authors.initials: J
authors.lastname: Reed
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004705:Endocytosis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D053763:Presenilins / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000172:deficiency* / Q000378:metabolism; D012995:Solubility
chemical_list: D016564:Amyloid beta-Protein Precursor; D053763:Presenilins; D023063:Receptors, Interleukin-8B; D053829:Amyloid Precursor Protein Secretases