APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice.
APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice.
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APOE4 通过下调 EFAD-Tg 小鼠的 NMDA 受体途径，增强年龄依赖性认知功能下降。
DOI：
10.1186/s13024-015-0002-2
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发表时间：
2015-03-05
影响因子：
15.1
通讯作者：
Chen XC
中科院分区：
文献类型：
--
作者：
Liu DS;Pan XD;Zhang J;Shen H;Collins NC;Cole AM;Koster KP;Ben Aissa M;Dai XM;Zhou M;Tai LM;Zhu YG;LaDu M;Chen XC
阿尔茨海默病（AD）导致记忆和认知的进行性丧失，并因AD的最大遗传风险因子APOE 4而加剧。载脂蛋白E（apoE）对认知的影响的一种提出的机制是通过NMDAR依赖性信号传导。使用EFAD转基因（Tg）小鼠（5xFAD小鼠，通过5种家族性AD（FAD）突变过度表达人淀粉样蛋白β（Aβ），并表达人apoE）和5xFAD/APOE敲除（KO）小鼠，分析APOE基因型对该途径的特异性影响。来自EFAD-Tg小鼠的先前数据证明了年龄依赖性（2-6个月）apoE特异性对Aβ病理学发展的影响。本研究通过比较E4 FAD小鼠与5xFAD/APOE-KO小鼠、E3 FAD和E2 FAD小鼠，检验了apoE 4通过调节NMDAR依赖性信号传导，特别是通过功能丧失损害认知的假设。使用2月龄、4月龄和6月龄的雌性E2 FAD、E3 FAD、E4 FAD和5xFAD/APOE-KO小鼠，将Y-迷宫和Morris水迷宫行为测试与突触蛋白水平结合作为突触活力的标志物。结果表明，与E2 FAD和E3 FAD小鼠相比，E4 FAD和5xFAD/APOE-KO小鼠中的年龄诱导的认知缺陷和PSD 95、dreplatin和NMDAR亚基减少更大，与apoE 4功能丧失一致。有趣的是，对于NMDAR介导的信号传导，p-CaMK-II的水平遵循与认知相同的apoE特异性模式，而p-CREB和BDNF的水平证明了apoE 4毒性功能获得：E2 FAD> E3 FAD> 5xFAD/APOE-KO > E4 FAD。这些发现表明，与E2 FAD和E3 FAD相比，E4 FAD和5xFAD/APOE-KO小鼠通过下调NMDAR信号通路表现出增强的年龄诱导的认知和关键突触蛋白降低，与apoE 4功能丧失一致。然而，p-CREB和BDNF的水平，多个途径共同的信号传导因子，表明毒性功能的获得。该领域的出版物提出了关于APOE 4是否赋予功能丧失或获得的矛盾结果。与本文报告的结果一样，载脂蛋白OE 4对特定的中枢神经系统特定措施的总体影响将是多种重叠机制的产物。因此，在确定APOE基因失活或纠正apoE 4相关正功能丧失的治疗是否是适当的治疗反应时，谨慎仍然至关重要。本文的在线版本（doi：10.1186/s13024-015-0002-2）包含补充材料，可供授权用户使用。
Alzheimer’s disease (AD) causes progressive loss of memory and cognition, exacerbated by APOE4, the greatest genetic risk factor for AD. One proposed mechanism for apolipoprotein E (apoE) effects on cognition is via NMDAR-dependent signaling. APOE genotype-specific effects on this pathway were dissected using EFAD-transgenic (Tg) mice (5xFAD mice, that over-express human amyloid-beta (Aβ) via 5 familial-AD (FAD) mutations, and express human apoE), and 5xFAD/APOE-knockout (KO) mice. Previous data from EFAD-Tg mice demonstrate age-dependent (2-6 months), apoE-specific effects on the development of Aβ pathology. This study tests the hypothesis that apoE4 impairs cognition via modulation of NMDAR-dependent signaling, specifically via a loss of function by comparison of E4FAD mice with 5xFAD/APOE-KO mice, E3FAD and E2FAD mice. Using female E2FAD, E3FAD, E4FAD and 5xFAD/APOE-KO mice aged 2-, 4-, and 6-months, the Y-maze and Morris water maze behavioral tests were combined with synaptic protein levels as markers of synaptic viability. The results demonstrate a greater age-induced deficit in cognition and reduction in PSD95, drebrin and NMDAR subunits in the E4FAD and 5xFAD/APOE-KO mice compared with E2FAD and E3FAD mice, consistent with an apoE4 loss of function. Interestingly, for NMDAR-mediated signaling, the levels of p-CaMK-II followed this same apoE-specific pattern as cognition, while the levels of p-CREB and BDNF demonstrate an apoE4 toxic gain of function: E2FAD > E3FAD > 5xFAD/APOE-KO > E4FAD. These findings suggest that compared with E2FAD and E3FAD, E4FAD and 5xFAD/APOE-KO mice exhibit enhanced age-induced reductions in cognition and key synaptic proteins via down-regulation of an NMDAR signaling pathway, consistent with an apoE4 loss of function. However, levels of p-CREB and BDNF, signaling factors common to multiple pathways, suggest a gain of toxic function. Publications in this field present contradictory results as to whether APOE4 imparts a loss or gain of function. As with the results reported herein, the overall effect of APOE4 on a given CNS-specific measure will be the product of multiple overlapping mechanisms. Thus, caution remains critical in determining whether APOE gene inactivation or therapies that correct the loss of positive function related to apoE4, are the appropriate therapeutic response. The online version of this article (doi:10.1186/s13024-015-0002-2) contains supplementary material, which is available to authorized users.
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DOI：
10.3233/jad-2010-101008
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Belinson H;Kariv-Inbal Z;Kayed R;Masliah E;Michaelson DM
通讯作者：
Michaelson DM
影响因子：
2.1
作者：
Bretsky, PM;Buckwalter, JG;Henderson, VW
通讯作者：
Henderson, VW
影响因子：
9.9
作者：
CORDER, EH;SAUNDERS, AM;HAINES, JL
通讯作者：
HAINES, JL
影响因子：
5.3
作者：
Boehm-Cagan, Anat;Michaelson, Daniel M.
通讯作者：
Michaelson, Daniel M.
影响因子：
2.7
作者：
Bour, Alexandra;Grootendorst, Jeannette;Mathis, Chantal
通讯作者：
Mathis, Chantal