A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity
A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity
复制标题
DOI：
10.1111/jnc.12717
复制
发表时间：
2014-07-01
影响因子：
4.7
通讯作者：
Matsuoka, Masaaki
中科院分区：
文献类型：
--
作者：
Hashimoto, Yuichi;Matsuoka, Masaaki
在体外，在没有淀粉样蛋白（a β）毒性参与的情况下，家族性阿尔茨海默病（AD）相关淀粉样蛋白β前体蛋白（APP）突变体的表达或转化生长因子β 2与野生型(wt)-APP的结合通过激活细胞内死亡信号（APP介导的细胞内死亡信号）导致神经元死亡。因此，这些神经元死亡模型可以被视为与AD相关的不依赖于A β的神经元死亡模型。最近的一项研究表明，APP异构体APP（770）中的A673T突变，与最普遍的神经元APP异构体APP（695）中的A598T突变（APP的AD保护突变）相对应，与AD发病率的降低有关。与此一致的是，表达ad保护突变体APP的细胞比表达wt-APP的细胞产生更少的A β。在本研究中，转化生长因子β 2在表达wt-APP的培养神经元细胞中引起死亡，而在表达APP AD保护突变体的培养神经元细胞中没有引起死亡。这表明APP AD保护突变通过减弱APP介导的细胞内死亡信号来降低AD的发病率。此外，一种导致遗传性脑出血伴淀粉样变性-荷兰型的突变也减弱了app介导的细胞内死亡信号。
Expression of a familial Alzheimer's disease (AD)-linked mutant of amyloid beta precursor protein (APP) or the binding of transforming growth factor beta 2 to wild-type (wt)-APP causes neuronal death by activating an intracellular death signal (a APP-mediated intracellular death signal) in the absence of the involvement of amyloid beta (A beta) toxicity in vitro. These neuronal death models may therefore be regarded as A beta-independent neuronal death models related to AD. A recent study has shown that the A673T mutation in the APP isoform APP(770), corresponding to the A598T mutation in the most prevalent neuronal APP isoform APP(695) (an AD-protective mutant of APP), is linked to a reduction in the incidence rate of AD. Consistent with this, cells expressing the AD-protective mutant of APP produce less A beta than cells expressing wt-APP. In this study, transforming growth factor beta 2 caused death in cultured neuronal cells expressing wt-APP, but not in those expressing the AD-protective mutant of APP. This result suggests that the AD-protective mutation of APP reduces the incidence rate of AD by attenuating the APP-mediated intracellular death signal. In addition, a mutation that causes hereditary cerebral hemorrhage with amyloidosis-Dutch type also attenuated the APP-mediated intracellular death signal.