Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology.
Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology.
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DOI：
10.1111/j.1582-4934.2008.00249.x
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发表时间：
2008-01
影响因子：
5.3
通讯作者：
Pei JJ
中科院分区：
文献类型：
--
作者：
Liu R;Zhou XW;Tanila H;Bjorkdahl C;Wang JZ;Guan ZZ;Cao Y;Gustafsson JA;Winblad B;Pei JJ
蛋白磷酸酶2A （PP2A）的下调被认为在阿尔茨海默病（AD）的tau过度磷酸化中起关键作用。体外Y307位点的PP2A催化亚基磷酸化有效地使PP2A失活。一种针对磷酸化(p) PP2A （Y307）的特异性抗体（PP2Ac-Yp307）被用来研究可能的PP2A下调与AD相关的已知病理生理变化，如Aβ积累和雌激素缺乏。免疫组织化学和免疫荧光共聚焦显微镜显示，PP2Ac-Yp307在大脑易感区域（如内鼻皮层和海马）的前缠结或缠结神经元中异常积累。实验中，与野生型相比，在稳定表达瑞典突变人淀粉样蛋白前体蛋白（APPswe）的小鼠N2a神经母细胞瘤细胞和转基因APPswe/早老素（PS1, A246E）小鼠的大脑中，PP2Ac-Yp307的表达增加，这与tau磷酸化增加相对应。用Aβ25-35处理N2a细胞可以模拟N2a APPswe细胞中PP2Ac-Yp307和tau磷酸化的变化。敲除雌激素受体(ER) α或ERβ后，小鼠脑内PP2Ac-Yp307水平和tau磷酸化发生类似变化。综上所述，这些发现表明，AD脑中Aβ沉积或雌激素缺乏可介导PP2A磷酸化（Y307）的增加，从而损害异常过度磷酸化的tau的去磷酸化，并导致神经原纤维缠结的形成。
Down-regulation of protein phosphatase 2A (PP2A) is thought to play a critical role in tau hyperphosphorylation in Alzheimer's disease (AD). In vitro phosphorylation of PP2A catalytic subunit at Y307 efficiently inactivates PP2A. A specific antibody against phosphorylated (p) PP2A (Y307) (PP2Ac-Yp307) was used to investigate possible PP2A down-regulation by known pathophysiological changes associated with AD, such as Aβ accumulation and oestrogen deficiency. Immunohistochemistry and immunofluorescence confocal microscopy showed an aberrant accumulation of PP2Ac-Yp307 in neurons that bear pretangles or tangles in the susceptible brain regions, such as the entorhinal cortical cortex and the hippocampus. Experimentally, increased PP2Ac-Yp307 was observed in mouse N2a neuroblastoma cells that stably express the human amyloid precursor protein with Swedish mutation (APPswe) compared with wild-type, and in the brains of transgenic APPswe/ presenilin (PS1, A246E) mice, which corresponded to the increased tau phosphorylation. Treating N2a cells with Aβ25–35 mimicked the changes of PP2Ac-Yp307 and tau phosphorylation in N2a APPswe cells. Knockout of oestrogen receptor (ER) α or ERβ gave similar changes of PP2Ac-Yp307 level and tau phosphorylation in the mouse brain. Taken together, these findings suggest that increased PP2A phosphorylation (Y307) can be mediated by Aβ deposition or oestrogen deficiency in the AD brain, and consequently compromise dephosphorylation of abnormally hyperphosphorylated tau, and lead to neurofibrillary tangle formation.
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DOI：
10.1016/j.molbrainres.2003.09.001
发表时间：
2003-11-26
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Ghribi, O;Prammonjago, P;Savory, J
通讯作者：
Savory, J
影响因子：
3.3
作者：
Pyo, HK;Lovati, E;Ksiezak-Reding, H
通讯作者：
Ksiezak-Reding, H
影响因子：
14.5
作者：
BRAUTIGAN, DL
通讯作者：
BRAUTIGAN, DL
DOI：
10.1073/pnas.0609663103
发表时间：
2006-12-19
影响因子：
11.1
作者：
Fan, Xiaotang;Warner, Margaret;Gustafsson, Jan-Ake
通讯作者：
Gustafsson, Jan-Ake
影响因子：
4.7
作者：
Liu, R;Pei, JJ;Wang, JZ
通讯作者：
Wang, JZ