Cell cycle-driven neuronal apoptosis specifically linked to amyloid peptide Aβ1-42 exposure is not exacerbated in a mouse model of presenilin-1 familial Alzheimer's disease
Cell cycle-driven neuronal apoptosis specifically linked to amyloid peptide Aβ1-42 exposure is not exacerbated in a mouse model of presenilin-1 familial Alzheimer's disease
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DOI：
10.1111/j.1471-4159.2008.05446.x
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发表时间：
2008-07-01
影响因子：
4.7
通讯作者：
Soriano, Salvador
中科院分区：
文献类型：
--
作者：
Malik, Bilal;Currais, Antonio;Soriano, Salvador
我们之前已经证明，在敲入模型（PS1 KIM146V小鼠）中携带家族性阿尔茨海默病（FAD）早老素-1 M146V突变的纯合子小鼠的皮质神经元中，β -连环蛋白和周期蛋白D1上调，导致细胞周期相关的凋亡。在这里，我们的目的是确定(i)这种表型是否存在于杂合子PS1 KIM146V小鼠中，它更准确地反映了人类的PS1 FAD状况；（ii） A β(1-42)是否总是存在于PS1 FAD大脑中，被认为影响神经元细胞周期动力学，可能导致PS1 KIM146V小鼠中出现的异常细胞周期/细胞死亡表型。我们证明，细胞周期相关的凋亡发生在杂合的PS1 KIM146V有丝分裂后神经元中。此外，在细胞周期和细胞死亡方面存在显著的a- β相关的增加，这不会被PS1 KIM146V突变进一步修饰。我们的研究结果与PS1 FAD脑中细胞周期相关的神经退行性变模型一致，其中PS1依赖性β -连环蛋白调节功能的丧失足以使易感神经元进入一个失败的细胞周期，并且可能与PS1 FAD脑中存在的a β细胞毒性挑战协同作用，以扩大易受细胞周期驱动的凋亡的神经元群体。
We have shown previously that beta-catenin and cyclin D1 are up-regulated in cortical neurons from homozygous mice carrying the familial Alzheimer's disease (FAD) presenilin-1 M146V mutation in a knock-in model (PS1 KIM146V mice), leading to cell cycle-associated apoptosis. Here, we have aimed to determine (i) whether this phenotype is present in heterozygous PS1 KIM146V mice, which reflects more accurately the PS1 FAD condition in humans and (ii) whether A beta(1-42), which is invariably present in the PS1 FAD brain and is thought to affect neuronal cell cycle kinetics, may contribute to the abnormal cell cycle/cell death phenotype seen in PS1 KIM146V mice. We demonstrate that cell cycle-linked apoptosis occurs in heterozygous PS1 KIM146V post-mitotic neurons. In addition, there is a significant A beta-associated increase in cell cycle and cell death that is not further modified by the PS1 KIM146V mutation. Our results are consistent with a cell cycle-associated neurodegeneration model in the PS1 FAD brain in which the loss of PS1-dependent beta-catenin regulatory function is sufficient to commit susceptible neurons to an abortive cell cycle, and may act synergistically with the A beta cytotoxic challenge present in the PS1 FAD brain to expand the neuronal population susceptible to cell cycle-driven apoptosis.