Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease
Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease
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DOI：
10.1523/jneurosci.5080-04.2005
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发表时间：
2005-05-25
影响因子：
5.3
通讯作者：
Savonenko, AV
中科院分区：
文献类型：
--
作者：
Jankowsky, JL;Melnikova, T;Savonenko, AV
流行病学研究表明，受过更高教育或从事对认知要求更高的职业的人患痴呆症的风险较小。我们想测试这种效应是否可以在啮齿动物中使用环境富集来重现，这是一种有据可查的减轻各种病理性损伤引起的行为缺陷的范例。在这里，我们证明了在阿尔茨海默病转基因小鼠模型中观察到的学习和记忆缺陷可以通过富集来改善。将过度表达淀粉样前体蛋白和/或早老素-1的雌性转基因小鼠和非转基因对照小鼠在2月龄时放入富集或标准笼中，并在6个月的差异饲养后测试认知行为。富集显着提高性能的所有基因型在径向水迷宫和经典的和重复反转版本的Morris水迷宫。然而，富集并不能使所有基因型都同样受益。过度产生淀粉样蛋白β（A β）的小鼠，特别是那些有淀粉样蛋白沉积的小鼠，在经典的Morris水迷宫中对平台位置的记忆较弱，在重复翻转任务中学习新平台位置的速度比非转基因笼鼠慢。尽管如此，富集使A β过度产生小鼠的表现正常化到标准饲养的非转基因小鼠的水平。此外，尽管双转基因动物海马中神经炎斑块负荷增加和稳态A β水平升高，但仍发生了这种功能保留，因为内源性和转基因衍生的A β在富集动物中均增加。这些结果表明，A β在体内的产生及其对神经系统功能的影响可以受到环境因素的强烈调节。
Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer's disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid-beta(A beta), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of A beta-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state A beta levels, because both endogenous and transgene-derived A beta are increased in enriched animals. These results demonstrate that the generation of A beta in vivo and its impact on the function of the nervous system can be strongly modulated by environmental factors.