Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production.
Age-related downregulation of the CaV3.1 T-type calcium channel as a mediator of amyloid beta production.
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DOI：
10.1016/j.neurobiolaging.2013.10.090
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发表时间：
2014-05
影响因子：
4.2
通讯作者：
Green KN
中科院分区：
文献类型：
--
作者：
Rice RA;Berchtold NC;Cotman CW;Green KN
阿尔茨海默氏症是一种严重影响老年人的神经退行性疾病。几十年的研究已经强调了在疾病之前和整个疾病期间发生的钙稳态中与年龄相关的变化，以及这种失调对阿尔茨海默病发病机制的贡献。我们报告了与年龄相关的CaV3.1 T型钙通道在人类和小鼠中信使RNA和蛋白质水平上的表达减少，这种减少随着阿尔茨海默病的存在而加剧。通过NNC-55-0396的药理学抑制作用下调N2 a细胞和阿尔茨海默病3xTg-AD小鼠模型中的T型钙通道，通过减少非淀粉样蛋白生成过程导致β淀粉样蛋白生成快速增加，而表达淀粉样蛋白前体蛋白的人胚肾细胞中通道的遗传过度表达产生互补效应。因此，年龄相关的CaV3.1表达下降可能有助于衰老大脑中的促淀粉样蛋白生成环境，并代表了干预阿尔茨海默病发病机制过程的新机会。
Alzheimer's is a crippling neurodegenerative disease that largely affects aged individuals. Decades of research have highlighted age-related changes in calcium homeostasis that occur before and throughout the duration of the disease, and the contributions of such dysregulation to Alzheimer's disease pathogenesis. We report an age-related decrease in expression of the CaV3.1 T-type calcium channel at the level of messenger RNA and protein in both humans and mice that is exacerbated with the presence of Alzheimer's disease. Downregulating T-type calcium channels in N2a cells and the 3xTg-AD mouse model of Alzheimer's disease, by way of pharmacologic inhibition with NNC-55-0396, results in a rapid increase in amyloid beta production via reductions in non-amyloidogenic processing, whereas genetic over-expression of the channel in human embryonic kidney cells expressing amyloid precursor protein produces complementary effects. The age-related decline in CaV3.1 expression may therefore contribute to a pro-amyloidogenic environment in the aging brain and represents a novel opportunity to intervene in the course of Alzheimer's disease pathogenesis.
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影响因子：
9.3
作者：
Cribbs DH;Berchtold NC;Perreau V;Coleman PD;Rogers J;Tenner AJ;Cotman CW
通讯作者：
Cotman CW
影响因子：
2.9
作者：
Emerick, Mark C.;Stein, Rebecca;Agnew, William S.
通讯作者：
Agnew, William S.
影响因子：
2.3
作者：
Iritani, S;Niizato, K;Emson, PC
通讯作者：
Emson, PC
DOI：
10.1016/j.bbrc.2006.06.096
发表时间：
2006-08-18
影响因子：
3.1
作者：
Morioka, Motohiro;Kawano, Takayuki;Kuratsu, Jun-ichi
通讯作者：
Kuratsu, Jun-ichi
DOI：
10.1124/jpet.103.060814
发表时间：
2004-04-01
影响因子：
3.5
作者：
Huang, LP;Keyser, BM;Li, M
通讯作者：
Li, M