Background:The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ). Objective:Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo. Methods:To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice. Results:We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments. Conclusion:These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ.

中文翻译：

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亮氨酸羧基甲基转移酶 1 过表达可防止 Tg2576 APP 转基因小鼠的认知和电生理损伤

背景：丝氨酸/苏氨酸蛋白磷酸酶 PP2A 被认为在阿尔茨海默病 (AD) 的分子发病机制中起核心作用，PP2A 的活性和底物特异性部分通过其催化的甲基化和去甲基化来调节。亚基。以前，我们发现 PP2A 甲基转移酶 LCMT-1 或 PP2A 甲基酯酶 PME-1 的转基因过表达改变了小鼠对急性暴露于合成寡聚淀粉样蛋白 β (Aβ) 引起的损伤的敏感性。目的：在这里，我们试图测试这些分子是否也能控制对体内产生的 Aβ 水平长期升高引起的损伤的敏感性。方法：为此，我们检查了转基因 LCMT-1 的影响，或 PME-1 过度表达对 Tg2576 小鼠中突变人 APP 慢性过度表达引起的认知和电生理损伤。结果：我们发现 LCMT-1 过表达可防止 Tg2576 小鼠的短期空间记忆和突触可塑性受损，而不会改变 APP 表达或可溶性 Aβ 水平。虽然 Tg2576 小鼠中 PME-1 过表达的影响程度很小，并且可能会被非认知障碍的出现混淆，但过表达 PME-1 的 Tg2576 小鼠显示出更早发作和/或认知和电生理严重程度增加的趋势。损伤。结论：这些数据表明 PP2A 甲基转移酶 LCMT-1 和 PP2A 甲基酯酶 PME-1，