Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer's disease are independent of caspase cleavage of the amyloid precursor protein.
Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer's disease are independent of caspase cleavage of the amyloid precursor protein.
复制标题
DOI：
10.1523/jneurosci.5341-09.2010
复制
发表时间：
2010-01-06
期刊：
影响因子：
--
通讯作者：
Mucke L
中科院分区：
文献类型：
--
作者：
Harris JA;Devidze N;Halabisky B;Lo I;Thwin MT;Yu GQ;Bredesen DE;Masliah E;Mucke L
以往的研究表明，半胱天冬酶对淀粉样前体蛋白（APP）天冬氨酸残基664的切割可能在阿尔茨海默病（AD）的发病机制中起关键作用。该位点（D 664 A）的突变阻止了caspase裂解和C-末端APP片段C31和Jcasp的产生，这些片段已被认为介导淀粉样蛋白-β（Aβ）神经毒性。在这里，我们在一系列测试中比较了具有（B254）和不具有（J20）D 664 A突变的人APP转基因小鼠。在Aβ沉积前，hAPP-B254和hAPP-J20小鼠的海马Aβ1-42水平相当。在2-3或5-7月龄时，hAPP-B254和hAPP-J20小鼠在空间和非空间学习和记忆、升高的十字迷宫性能、突触传递和可塑性的电生理测量以及突触活性相关蛋白的水平方面相对于非转基因小鼠具有相似的异常。因此，APP在位置D 664处的半胱天冬酶切割和C31的产生在这些异常的发展中不起关键作用。
Previous studies suggested that cleavage of the amyloid precursor protein (APP) at aspartate residue 664 by caspases may play a key role in the pathogenesis of Alzheimer’s disease (AD). Mutation of this site (D664A) prevents caspase cleavage and the generation of the C-terminal APP fragments C31 and Jcasp, which have been proposed to mediate amyloid-β (Aβ) neurotoxicity. Here we compared human APP transgenic mice with (B254) and without (J20) the D664A mutation in a battery of tests. Before Aβ deposition, hAPP-B254 and hAPP-J20 mice had comparable hippocampal levels of Aβ1-42. At 2–3 or 5–7 months of age, hAPP-B254 and hAPP-J20 mice had similar abnormalities relative to non-transgenic mice in spatial and non-spatial learning and memory, elevated plus maze performance, electrophysiological measures of synaptic transmission and plasticity, and levels of synaptic activity-related proteins. Thus, caspase cleavage of APP at position D664 and generation of C31 do not play a critical role in the development of these abnormalities.