Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice.
Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice.
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早期生活压力导致中年 ApoE4-TR 小鼠空间学习和记忆受损
DOI：
10.1186/s13024-016-0107-2
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发表时间：
2016-07-12
影响因子：
15.1
通讯作者：
Chen XC
中科院分区：
文献类型：
--
作者：
Lin LY;Zhang J;Dai XM;Xiao NA;Wu XL;Wei Z;Fang WT;Zhu YG;Chen XC
载脂蛋白E(ApoE)是支持脑内脂质转运和损伤修复的主要脂质载体。载脂蛋白Eε4等位基因与抑郁症、轻度认知障碍和痴呆症有关；然而，载脂蛋白E4影响疾病发展风险的确切分子机制尚不清楚。为了解决这一认识上的差距，我们调查了慢性不可预测的温和应激(CUMS)对ApoE3和ApoE4靶标替换(ApoE3-tr和ApoE4-tr)小鼠的潜在影响。所有3个月大的暴露于CUMS的ApoE-tr小鼠在12个月大时都从抑郁样状态中恢复过来。值得注意的是，ApoE4-tr小鼠与年龄匹配的ApoE3-tr小鼠不同，表现出空间认知能力受损，GABA能神经元丢失，Reelin、PSD95、SYN和Fyn表达减少，NMDAR2B和CREB磷酸化减少。这些结果表明，早期应激可能通过GABA能神经元和Reelin表达的持续减少，进一步降低Fyn/NMDAR2B信号通路的激活，从而介导中年ApoE4-tr小鼠的认知损害。
Apolipoprotein E (ApoE) is a major lipid carrier that supports lipid transport and injury repair in the brain. The APOE ε4 allele is associated with depression, mild cognitive impairment (MCI) and dementia; however, the precise molecular mechanism through which ApoE4 influences the risk of disease development remains unknown. To address this gap in knowledge, we investigated the potential effects of chronic unpredictable mild stress (CUMS) on ApoE3 and ApoE4 target replacement (ApoE3-TR and ApoE4-TR) mice. All ApoE-TR mice exposed to CUMS at 3 months old recovered from a depression-like state by the age of 12 months. Of note, ApoE4-TR mice, unlike age-matched ApoE3-TR mice, displayed impaired spatial cognitive abilities, loss of GABAergic neurons, decreased expression of Reelin, PSD95, SYN and Fyn, and reduced phosphorylation of NMDAR2B and CREB. These results suggest that early-life stress may mediate cognitive impairment in middle-age ApoE4-TR mice through sustained reduction of GABAergic neurons and Reelin expression, which might further diminish the activation of the Fyn/NMDAR2B signaling pathway.