Navβ2 knockdown improves cognition in APP/PS1 mice by partially inhibiting seizures and APP amyloid processing.
Navβ2 knockdown improves cognition in APP/PS1 mice by partially inhibiting seizures and APP amyloid processing.
复制标题
Nav beta 2 敲除通过部分抑制癫痫发作和 APP 淀粉样蛋白加工来改善 APP/PS1 小鼠的认知能力
DOI：
10.18632/oncotarget.21849
复制
发表时间：
2017-11-21
期刊：
影响因子：
--
通讯作者：
Xiyang YB
中科院分区：
文献类型：
--
作者：
Hu T;Xiao Z;Mao R;Chen B;Lu MN;Tong J;Mei R;Li SS;Xiao ZC;Zhang LF;Xiyang YB
电压门控钠通道β2(NaVβ2，由β2B编码)是淀粉样前体蛋白裂解酶1(BACE1)的底物，调节神经元细胞表面通道的表达。以前的研究报道，在阿尔茨海默病(AD)模型和患者中，BACE1增强了Navβ2的处理。我们研究了NAVβ2表达的变化是否影响AD小鼠模型中神经元癫痫发作和淀粉样前体蛋白(APP)的处理。我们的研究使用了8月龄的APP/早老素1(PS1)小鼠和转基因NAVβ2基因敲除的APP/PS1小鼠(APP/PS1/NAVβ2-kd)，以及年龄匹配的野生型和NAVβ2基因敲除(NAVβ2-kd)小鼠作为对照。我们发现，在APP/PS1小鼠中，NAVβ2基因敲除部分逆转了NAVβ2的异常裂解以及细胞内和总Nav1.1α表达的变化。它还恢复了脑电跟踪显示的海马神经元钠电流密度和神经元活动；改善了Morris水迷宫的性能；并将APP淀粉样变性代谢转向非淀粉样变性代谢。WT小鼠和NAVβ2-kd小鼠在这些指标上没有差异。这些结果表明，NAVβ2基因敲除可能是治疗AD的一种有前途的策略。
Voltage-gated sodium channels beta 2 (Navβ2, encoded by SCN2B) is a substrate of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and regulates cell surface expression of channels in neurons. Previous studies reported enhanced Navβ2 processing by BACE1 in Alzheimer’s disease (AD) model and patients. We investigated whether changes in Navβ2 expression affect neuronal seizure and amyloid precursor protein (APP) processing in an AD mouse model. Our study used eight-month-old APP/presenilin 1 (PS1) mice and transgenic Navβ2 knockdown [by 61% vs. wild type (WT)] APP/PS1 mice (APP/PS1/Navβ2-kd), with age-matched WT and Navβ2 knockdown (Navβ2-kd) mice as controls. We found that Navβ2 knockdown in APP/PS1 mice partially reversed the abnormal Navβ2 cleavage and the changes in intracellular and total Nav1.1α expression. It also restored sodium currents density in hippocampal neurons and neuronal activity, as indicated by EEG tracing; improved Morris water maze performance; and shifted APP amyloidogenic metabolism towards non-amyloidogenic processing. There were no differences in these indicators between WT and Navβ2-kd mice. These results suggest Navβ2 knockdown may be a promising strategy for treating AD.
登录
查看更多内容
影响因子：
5.7
作者：
Gordon JA
通讯作者：
Gordon JA
影响因子：
168.9
作者：
Ballard, Clive;Gauthier, Serge;Jones, Emma
通讯作者：
Jones, Emma
影响因子：
3.5
作者：
Tamagnini F;Scullion S;Brown JT;Randall AD
通讯作者：
Randall AD
影响因子：
4.8
作者：
Kazim SF;Chuang SC;Zhao W;Wong RK;Bianchi R;Iqbal K
通讯作者：
Iqbal K
影响因子：
--
作者：
Ebbert MT;Ridge PG;Kauwe JS
通讯作者：
Kauwe JS