Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice
Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice
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DOI：
10.1016/j.neurobiolaging.2007.12.022
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发表时间：
2009-11-01
影响因子：
4.2
通讯作者：
McDonald, Michael P.
中科院分区：
文献类型：
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作者：
Bernardo, Alexandra;Harrison, Fiona E.;McDonald, Michael P.
神经节苷脂已被证明是 β-淀粉样蛋白 (Aβ) 结合和聚集所必需的。 GD3 合酶 (GD3S) 负责 b 系列和 c 系列神经节苷脂的生物合成，包括四种主要脑神经节苷脂中的两种。我们检查了缺乏 GD3S (St8sia1) 编码基因的小鼠神经组织中的 A β-神经节苷脂相互作用，以及与 GD3S-/- 小鼠杂交的阿尔茨海默病双转基因 (APP/PSEN1) 小鼠模型。在缺乏 GD3S 的原代神经元和星形胶质细胞中，Aβ 诱导的细胞死亡和 Aβ 聚集受到抑制。与GD3S-/-和APP/PSEN1双转基因小鼠一样，APP/PSENI/GD3S-/-“三重突变”小鼠在随意检查时与野生型小鼠没有区别。 APP/PSEN1 双转基因在许多参考记忆任务中表现出严重的损伤。相比之下，APP/PSEN1/GD3S-/- 三重突变小鼠的表现与野生型对照和 GD3S-/- 小鼠一样好。与行为改善一致的是，在三重突变小鼠中，聚集和未聚集的 Aβ 以及相关的神经病理学几乎完全消除。这些结果表明，GD3 合酶可能是对抗阿尔茨海默病患者认知缺陷、淀粉样蛋白斑形成和神经变性的新治疗靶点。 (C) 2008 年，爱思唯尔公司出版。
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.