title: Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease.
abstract: We present evidence here that exosomes stimulate aggregation of amyloid beta (Aβ)1-42 in vitro and in vivo and interfere with uptake of Aβ by primary cultured astrocytes and microglia in vitro. Exosome secretion is prevented by the inhibition of neutral sphingomyelinase 2 (nSMase2), a key regulatory enzyme generating ceramide from sphingomyelin, with GW4869. Using the 5XFAD mouse, we show that intraperitoneal injection of GW4869 reduces the levels of brain and serum exosomes, brain ceramide, and Aβ1-42 plaque load. Reduction of total Aβ1-42 as well as number of plaques in brain sections was significantly greater (40% reduction) in male than female mice. Our results suggest that GW4869 reduces amyloid plaque formation in vivo by preventing exosome secretion and identifies nSMase2 as a potential drug target in AD by interfering with exosome secretion.
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dinkins
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA, USA.
authors.forename: Somsankar
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA, USA.
authors.forename: Guanghu
authors.initials: G
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA, USA.
authors.forename: Gu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA, USA. Electronic address: ebieberich@gmail.com.
authors.forename: Erhard
authors.initials: E
authors.lastname: Bieberich
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001597:Benzylidene Compounds / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism*; D066263:Protein Aggregation, Pathological; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D001597:Benzylidene Compounds; D002518:Ceramides; C468773:GW 4869; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase
keywords: Alzheimer's disease; Amyloid beta; Astrocytes; Exosomes; GW4869; Neutral sphingomyelinase; Primary culture