Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice

Abstract 

Gangliosides have been shown to be necessary for β-amyloid (Aβ) 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 Aβ-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, Aβ-induced cell death and Aβ 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 Aβ 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.

Keywords: Alzheimer's disease, Behavior, Memory, Aβ, Gangliosides, GM1, GD3 synthase, Plaque, Amyloid precursor protein, GD1a, GD1b GT1b, GD3, Apoptosis, Oxidative stress, Neuroinflammation, Lipid rafts