Silencing [Formula: see text] Rescues Tau Pathologies and Memory Deficits through Rescuing PP2A and Inhibiting GSK-3β Signaling in Human Tau Transgenic Mice.
Silencing [Formula: see text] Rescues Tau Pathologies and Memory Deficits through Rescuing PP2A and Inhibiting GSK-3β Signaling in Human Tau Transgenic Mice.
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DOI：
10.3389/fnagi.2014.00123
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发表时间：
2014
影响因子：
4.8
通讯作者：
Liu GP
中科院分区：
文献类型：
--
作者：
Zhang Y;Ma RH;Li XC;Zhang JY;Shi HR;Wei W;Luo DJ;Wang Q;Wang JZ;Liu GP
蛋白磷酸酶-2A抑制剂-2的增加与阿尔茨海默病（AD）中蛋白磷酸酶-2A（PP 2A）抑制和tau蛋白过度磷酸化相关。下调表达淀粉样蛋白前体蛋白（tg 2576）的转基因小鼠中淀粉样蛋白的生成并改善其认知功能。在这里，我们发现，在12个月大的人tau转基因小鼠中，通过海马输注的沉默下调（~45%），减少tau磷酸化/积累，改善记忆缺陷和树突可塑性。沉默PP 2A不仅恢复了PP 2A的活性，而且还抑制了糖原合成酶激酶-3 β（GSK-3β），并显著激活了蛋白激酶A（PKA）和Akt。在HEK 293/tau和N2 a/tau细胞中，沉默也显著降低了tau过度磷酸化，恢复了PP 2A活性并抑制了GSK-3β，表现为GSK-3β总蛋白和mRNA水平降低，以及GSK-3β丝氨酸-9抑制性磷酸化增加。此外，PKA而不是Akt的激活通过沉默介导GSK-3β的抑制。我们的结论是，靶向可以改善人tau转基因小鼠的tau病理和记忆缺陷，并且PKA的激活有助于体外沉默诱导的GSK-3β抑制，这表明PKA是AD的有希望的多靶点。
Increase of inhibitor-2 of protein phosphatase-2A is associated with protein phosphatase-2A (PP2A) inhibition and tau hyperphosphorylation in Alzheimer’s disease (AD). Down-regulating attenuated amyloidogenesis and improved the cognitive functions in transgenic mice expressing amyloid precursor protein (tg2576). Here, we found that silencing by hippocampal infusion of down-regulated (~45%) with reduction of tau phosphorylation/accumulation, improvement of memory deficits, and dendritic plasticity in 12-month-old human tau transgenic mice. Silencing not only restored PP2A activity but also inhibited glycogen synthase kinase-3β (GSK-3β) with a significant activation of protein kinase A (PKA) and Akt. In HEK293/tau and N2a/tau cells, silencing by also significantly reduced tau hyperphosphorylation with restoration of PP2A activity and inhibition of GSK-3β, demonstrated by the decreased GSK-3β total protein and mRNA levels, and the increased inhibitory phosphorylation of GSK-3β at serine-9. Furthermore, activation of PKA but not Akt mediated the inhibition of GSK-3β by silencing. We conclude that targeting can improve tau pathologies and memory deficits in human tau transgenic mice, and activation of PKA contributes to GSK-3β inhibition induced by silencing in vitro, suggesting that is a promising multiple target of AD.
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DOI：
10.1073/pnas.1322614111
发表时间：
2014-01-21
影响因子：
11.1
作者：
Arif, Mohammad;Kazim, Syed Faraz;Iqbal, Khalid
通讯作者：
Iqbal, Khalid
影响因子：
4.8
作者：
Bradley CA;Peineau S;Taghibiglou C;Nicolas CS;Whitcomb DJ;Bortolotto ZA;Kaang BK;Cho K;Wang YT;Collingridge GL
通讯作者：
Collingridge GL
DOI：
10.1073/pnas.220413597
发表时间：
2000-10-24
影响因子：
11.1
作者：
Fang, XJ;Yu, SX;Mills, GB
通讯作者：
Mills, GB
影响因子：
30.8
作者：
Emamian, ES;Hall, D;Gogos, JA
通讯作者：
Gogos, JA
影响因子：
3.5
作者：
ISHIGURO, K;SHIRATSUCHI, A;IMAHORI, K
通讯作者：
IMAHORI, K