Journal
NEUROBIOLOGY OF AGING
Volume 30, Issue 11, Pages 1777-1791Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.12.022
Keywords
Alzheimer's disease; Behavior; Memory; A beta; Gangliosides; GM1; GD3 synthase; Plaque; Amyloid precursor protein; GD1a; GD1b GT1b; GD3; Apoptosis; Oxidative stress; Neuroinflammation; Lipid rafts
Categories
Funding
- National Institute of Aging [AG022439, AG022455, AG023597]
- National Institute of Neurological Disorders and Stroke [NS04520]
- National Institute of General Medical Sciences [GM42056]
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Gangliosides have been shown to be necessary for beta-amyloid (A beta) 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 A beta-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, A beta-induced cell death and A beta aggregation were inhibited. Like GD3S-/- and APP/PSEN1 double-transgenic mice, APP/PSENI/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 A beta 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. (C) 2008 Published by Elsevier Inc.
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