title: Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice.
abstract: Gangliosides have been shown to be necessary for beta-amyloid (Abeta) binding and aggregation. GD3 synthase (GD3S) is responsible for biosynthesis of the b- and c-series gangliosides, including two of the four major brain gangliosides. We examined Abeta-ganglioside interactions in neural tissue from mice lacking the gene coding for GD3S (St8sia1), and in a double-transgenic (APP/PSEN1) mouse model of Alzheimer's disease cross-bred with GD3S-/- mice. In primary neurons and astrocytes lacking GD3S, Abeta-induced cell death and Abeta aggregation were inhibited. Like GD3S-/- and APP/PSEN1 double-transgenic mice, APP/PSEN1/GD3S-/- "triple-mutant" mice are indistinguishable from wild-type mice on casual examination. APP/PSEN1 double-transgenics exhibit robust impairments on a number of reference-memory tasks. In contrast, APP/PSEN1/GD3S-/- triple-mutant mice performed as well as wild-type control and GD3S-/- mice. Consistent with the behavioral improvements, both aggregated and unaggregated Abeta and associated neuropathology were almost completely eliminated in triple-mutant mice. These results suggest that GD3 synthase may be a novel therapeutic target to combat the cognitive deficits, amyloid plaque formation, and neurodegeneration that afflict Alzheimer's patients.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN, United States.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bernardo
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Harrison
authors.forename: Meghan
authors.initials: M
authors.lastname: McCord
authors.forename: Jiali
authors.initials: J
authors.lastname: Zhao
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bruchey
authors.forename: Sean S
authors.initials: SS
authors.lastname: Davies
authors.forename: L
authors.initials: L
authors.lastname: Jackson Roberts
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Toshio
authors.initials: T
authors.lastname: Ariga
authors.forename: Robert K
authors.initials: RK
authors.lastname: Yu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Thompson
authors.forename: Michael P
authors.initials: MP
authors.lastname: McDonald
mesh_terms: D000544:Alzheimer Disease; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D058225:Plaque, Amyloid / Q000235:genetics / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012799:Sialyltransferases / Q000172:deficiency*
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D039481:CD11b Antigen; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase