Reduced expression of Na+ /Ca2+ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice
Reduced expression of Na+ /Ca2+ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice
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Na /Ca2 交换蛋白表达减少与阿尔茨海默病模型小鼠的认知缺陷有关
DOI：
10.1016/j.neuropharm.2017.12.037
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发表时间：
2018
影响因子：
4.7
通讯作者：
Fukunaga K
中科院分区：
文献类型：
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作者：
Moriguchi S;Kita S;Fukaya M;Osanai M;Inagaki R;Sasaki Y;Izumi H;Horie K;Takeda J;Saito T;Sakagami H;Saido TC;Iwamoto T;Fukunaga K
Na+/Ca 2+交换剂（NCX）主要在大多数细胞类型的质膜中表达，其中它们介导一个Ca 2+对三个Na+离子的产电交换，这取决于跨膜的Ca 2+和Na+电化学梯度。三种哺乳动物NCX同种型（NCX 1、NCX 2和NCX 3）各自由不同的基因编码。在此，我们报道了在APP 23和APP-KI小鼠海马CA 1区，NCX 2和NCX 3蛋白和mRNA水平相对降低。同样，NCX 2 +/−或NCX 3 +/−小鼠表现出海马LTP和记忆相关行为受损。此外，与对照组相比，NCX 2 +/−小鼠海马中钙/钙调蛋白依赖性蛋白激酶II（CaMK II）自磷酸化显著降低，但NCX 3 +/−小鼠海马中CaMK II自磷酸化增加。NCX 2或NCX 3杂合子表现出海马LTP维持受损，这一表型在NCX 2 +/−小鼠中与钙调磷酸酶（CaN）活性升高相关，并通过钙调磷酸酶（CaN）抑制剂FK 506治疗得以挽救。同样，FK 506治疗显著恢复了APP-KI小鼠受损的海马LTP。此外，在NCX 2 +/−小鼠的海马CA 1区，高频刺激后去极化后的Ca 2+清除略有延迟。电子显微镜显示，NCX 2 +/−小鼠的CA 1区突触密度相对降低，而NCX 3 +/−小鼠的CA 1区穿孔突触棘的数量显著增加。我们的结论是，在NCX 2 +/−和NCX 3 +/−小鼠中观察到的记忆障碍反映了海马CaMKII活性失调，这改变了树突棘形态，这一发现与阿尔茨海默病模型小鼠中观察到的记忆缺陷有关。
Na+/Ca2+exchangers (NCXs) are expressed primarily in the plasma membrane of most cell types, where they mediate electrogenic exchange of one Ca2+for three Na+ions, depending on Ca2+and Na+electrochemical gradients across the membrane. Three mammalian NCX isoforms (NCX1, NCX2, and NCX3) are each encoded by a distinct gene. Here, we report that NCX2 and NCX3 protein and mRNA levels are relatively reduced in hippocampal CA1 ofAPP23andAPP-KI mice. Likewise,NCX2+/−orNCX3+/−mice exhibited impaired hippocampal LTP and memory-related behaviors. Moreover, relative to controls, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased inNCX2+/−mouse hippocampus but increased in hippocampus ofNCX3+/−mice.NCX2orNCX3heterozygotes displayed impaired maintenance of hippocampal LTP, a phenotype that inNCX2+/−mice was correlated with elevated calcineurin activity and rescued by treatment with the calcineurin (CaN) inhibitor FK506. Likewise, FK506 treatment significantly restored impaired hippocampal LTP inAPP-KI mice. Moreover, Ca2+clearance after depolarization following high frequency stimulation was slightly delayed in hippocampal CA1 regions ofNCX2+/−mice. Electron microscopy revealed relatively decreased synaptic density in CA1 ofNCX2+/−mice, while the number of spines with perforated synapses in CA1 significantly increased inNCX3+/−mice. We conclude that memory impairment seen inNCX2+/−andNCX3+/−mice reflect dysregulated hippocampal CaMKII activity, which alters dendritic spine morphology, findings with implications for memory deficits seen in Alzheimer's disease model mice.