Alzheimer Abeta peptide induces chromosome mis-segregation and aneuploidy, including trisomy 21: requirement for tau and APP.
Alzheimer Abeta peptide induces chromosome mis-segregation and aneuploidy, including trisomy 21: requirement for tau and APP.
复制标题
DOI：
10.1091/mbc.e09-10-0850
复制
发表时间：
2010-02-15
影响因子：
3.3
通讯作者：
Potter H
中科院分区：
文献类型：
--
作者：
Granic A;Padmanabhan J;Norden M;Potter H
染色体非整倍体，尤其是21三体，在家族性和散发性阿尔茨海默病中均可发生。FAD基因的表达或暴露于Aβ肽可诱导TG小鼠和培养细胞的非整倍体。在Aβ诱导的染色体错误分离中，对葛兰素史克-3β、钙蛋白酶和牛磺酸的需求表明MT功能障碍是AD发病的原因之一。散发性和家族性阿尔茨海默病(AD)患者在神经元和其他细胞中都表现出染色体非整倍体增加，特别是21三体。值得注意的是，21三体/唐氏综合征患者发生早发性AD病理。我们研究了阿尔茨海默病中镶嵌染色体非整倍体的机制，并报道了阿尔茨海默病淀粉样前体蛋白基因APP的FAD突变在转基因小鼠和转基因细胞中导致染色体错误分离和非整倍体。此外，在培养细胞中加入APP的致病产物人工合成的Aβ肽，会导致快速而强烈的染色体错误分离，导致非整倍体，包括三体21，Daughters，这可通过添加LiCl2或钙离子螯合来阻止，并在tau KO细胞中复制，暗示β-3 GSK-3β、钙蛋白酶和依赖于Tau的微管运输参与了A GSK-3的非整倍体活性。此外，APP KO细胞对Aβ的非优生活性具有抵抗力，因为已有研究表明它们对Aβ诱导的tau磷酸化和细胞毒性具有抵抗力。这些结果表明，Aβ诱导的微管功能障碍导致非整倍体神经元，从而可能参与AD的发病机制。
Chromosome aneuploidy, especially trisomy 21, arises in both familial and sporadic Alzheimer's disease. Expression of FAD genes or exposure to Aβ peptide induces aneuploidy in tg-mice and cultured cells. The requirement for GSK-3β, calpain, and Tau in Aβ-induced chromosome mis-segregation points to MT dysfunction as contributing to AD pathogenesis. Both sporadic and familial Alzheimer's disease (AD) patients exhibit increased chromosome aneuploidy, particularly trisomy 21, in neurons and other cells. Significantly, trisomy 21/Down syndrome patients develop early onset AD pathology. We investigated the mechanism underlying mosaic chromosome aneuploidy in AD and report that FAD mutations in the Alzheimer Amyloid Precursor Protein gene, APP, induce chromosome mis-segregation and aneuploidy in transgenic mice and in transfected cells. Furthermore, adding synthetic Aβ peptide, the pathogenic product of APP, to cultured cells causes rapid and robust chromosome mis-segregation leading to aneuploid, including trisomy 21, daughters, which is prevented by LiCl addition or Ca2+ chelation and is replicated in tau KO cells, implicating GSK-3β, calpain, and Tau-dependent microtubule transport in the aneugenic activity of Aβ. Furthermore, APP KO cells are resistant to the aneugenic activity of Aβ, as they have been shown previously to be resistant to Aβ-induced tau phosphorylation and cell toxicity. These results indicate that Aβ-induced microtubule dysfunction leads to aneuploid neurons and may thereby contribute to the pathogenesis of AD.
登录
查看更多内容
影响因子：
64.5
作者：
Li, JH;Xu, M;Potter, H
通讯作者：
Potter, H
DOI：
10.1111/j.1749-6632.1996.tb34408.x
发表时间：
1996-01-01
期刊：
NEUROBIOLOGY OF ALZHEIMER'S DISEASE
影响因子：
--
作者：
Lee, VMY
通讯作者：
Lee, VMY
影响因子：
82.9
作者：
Chui, DH;Tanahashi, H;Tabira, T
通讯作者：
Tabira, T
影响因子：
2.9
作者：
Chromy, BA;Nowak, RJ;Klein, WL
通讯作者：
Klein, WL
影响因子：
2.5
作者：
Kulnane, LS;Lehman, EJH;Lamb, BT
通讯作者：
Lamb, BT