Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex
Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex
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DOI：
10.1101/lm.030031.112
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发表时间：
2013-05-01
影响因子：
2
通讯作者：
Rebeck, G. William
中科院分区：
文献类型：
--
作者：
Rodriguez, Gustavo A.;Burns, Mark P.;Rebeck, G. William
载脂蛋白E4(apoE-(Epsilon)4)等位基因是晚发性阿尔茨海默病的最强遗传风险因素，可能通过影响早期正常大脑功能而使个体易患阿尔茨海默病相关的认知功能下降。为了研究人类载脂蛋白E等位基因对小鼠认知能力的影响，我们在巴恩斯迷宫中训练了3个月大的载脂蛋白E靶向替换小鼠(E2、E3和E4)，以定位并进入迷宫周边的靶洞。分别于训练后24小时和72小时检测大鼠的长期空间记忆。我们发现，年轻的E4小鼠在巴恩斯迷宫中的空间学习和记忆能力明显低于E3小鼠。在18个月大的E4小鼠的第二个独立队列中，也存在空间认知缺陷。相比之下，在隐藏平台水迷宫中，APOE基因对认知表现的影响不是很大。我们还研究了3个月大的tr小鼠内侧内嗅觉皮质神经元的树突形态，这些神经元对空间学习功能很重要。我们发现，与E3小鼠相比，E4小鼠的基干树突中的树突明显更短，棘突密度更低，这与E4小鼠的空间学习和记忆缺陷是一致的。这些发现表明，人类apoE-(Epsilon)4可能会影响生命早期的认知功能和神经元形态。
The apolipoprotein E4 (APOE-(epsilon)4) allele is the strongest genetic risk factor for developing late-onset Alzheimer's disease, and may predispose individuals to Alzheimer's-related cognitive decline by affecting normal brain function early in life. To investigate the impact of human APOE alleles on cognitive performance in mice, we trained 3-mo-old APOE targeted replacement mice (E2, E3, and E4) in the Barnes maze to locate and enter a target hole along the perimeter of the maze. Long-term spatial memory was probed 24 h and 72 h after training. We found that young E4 mice exhibited significantly impaired spatial learning and memory in the Barnes maze compared to E3 mice. Deficits in spatial cognition were also present in a second independent cohort of E4 mice tested at 18 mo of age. In contrast, cognitive performance in the hidden platform water maze was not as strongly affected by APOE genotype. We also examined the dendritic morphology of neurons in the medial entorhinal cortex of 3-mo-old TR mice, neurons important to spatial learning functions. We found significantly shorter dendrites and lower spine densities in basal shaft dendrites of E4 mice compared to E3 mice, consistent with spatial learning and memory deficits in E4 animals. These findings suggest that human APOE-(epsilon)4 may affect cognitive function and neuronal morphology early in life.