Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic mice
Increase of inhibitor-2 of protein phosphatase-2A (I2PP2A) is associated with PP2A inhibition and tau hyperphosphorylation in Alzheimer’s disease (AD). Down-regulating I2PP2A attenuated amyloidogenesis and improved the cognitive functions in transgenic mice expressing amyloid precursor protein (tg25...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-06-01
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| Series: | Frontiers in Aging Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00123/full |
| _version_ | 1811223083885789184 |
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| author | Yao eZhang Yao eZhang Yao eZhang Rong-Hong eMa Rong-Hong eMa Xia-Chun eLi Jia-Yu eZhang Hai-Rong eShi Wei eWei Wei eWei Dan-Ju eLuo Qun eWang Jian-Zhi eWang Gong-Ping eLiu |
| author_facet | Yao eZhang Yao eZhang Yao eZhang Rong-Hong eMa Rong-Hong eMa Xia-Chun eLi Jia-Yu eZhang Hai-Rong eShi Wei eWei Wei eWei Dan-Ju eLuo Qun eWang Jian-Zhi eWang Gong-Ping eLiu |
| author_sort | Yao eZhang |
| collection | DOAJ |
| description | Increase of inhibitor-2 of protein phosphatase-2A (I2PP2A) is associated with PP2A inhibition and tau hyperphosphorylation in Alzheimer’s disease (AD). Down-regulating I2PP2A attenuated amyloidogenesis and improved the cognitive functions in transgenic mice expressing amyloid precursor protein (tg2576). Here, we found that silencing I2PP2A by hippocampal infusion of Lenti-siI2PP2A downregulated I2PP2A (~45%) with reduction of tau phosphorylation/accumulation, improvement of memory deficits and dendritic plasticity in 12-month old human tau transgenic mice. Silencing I2PP2A 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 I2PP2A by pSUPER-siI2PP2A 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 I2PP2A silencing. We conclude that targeting I2PP2A can improve tau pathologies and memory deficits in htau transgenic mice, and activation of PKA contributes to GSK-3β inhibition induced by silencing I2PP2A in vitro, suggesting that I2PP2A is a promising multiple target of AD. |
| first_indexed | 2024-04-12T08:26:56Z |
| format | Article |
| id | doaj.art-ed30b5bf972e4eab87ceb2885719f6dd |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-04-12T08:26:56Z |
| publishDate | 2014-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-ed30b5bf972e4eab87ceb2885719f6dd2022-12-22T03:40:22ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652014-06-01610.3389/fnagi.2014.0012389438Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic miceYao eZhang0Yao eZhang1Yao eZhang2Rong-Hong eMa3Rong-Hong eMa4Xia-Chun eLi5Jia-Yu eZhang6Hai-Rong eShi7Wei eWei8Wei eWei9Dan-Ju eLuo10Qun eWang11Jian-Zhi eWang12Gong-Ping eLiu13Key Laboratory of Neurological Disease of Chinese Ministry of EducationLiyuan HospitalHuazhong University of Science and TechnologyHuazhong University of Science and TechnologyXiehe HospitalHuazhong University of Science and TechnologyHuazhong University of Science and TechnologyHuazhong University of Science and TechnologyHuazhong University of Science and TechnologyDepartment of Pathophysiology, Jinan University,Huazhong University of Science and TechnologyHuazhong University of Science and TechnologyHuazhong University of Science and TechnologyHuazhong University of Science and TechnologyIncrease of inhibitor-2 of protein phosphatase-2A (I2PP2A) is associated with PP2A inhibition and tau hyperphosphorylation in Alzheimer’s disease (AD). Down-regulating I2PP2A attenuated amyloidogenesis and improved the cognitive functions in transgenic mice expressing amyloid precursor protein (tg2576). Here, we found that silencing I2PP2A by hippocampal infusion of Lenti-siI2PP2A downregulated I2PP2A (~45%) with reduction of tau phosphorylation/accumulation, improvement of memory deficits and dendritic plasticity in 12-month old human tau transgenic mice. Silencing I2PP2A 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 I2PP2A by pSUPER-siI2PP2A 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 I2PP2A silencing. We conclude that targeting I2PP2A can improve tau pathologies and memory deficits in htau transgenic mice, and activation of PKA contributes to GSK-3β inhibition induced by silencing I2PP2A in vitro, suggesting that I2PP2A is a promising multiple target of AD.http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00123/fullAlzheimer DiseaseMemorytau hyperphosphorylationinhibitor-2 of protein phosphatase-2Aglycogen synthase kinase 3β |
| spellingShingle | Yao eZhang Yao eZhang Yao eZhang Rong-Hong eMa Rong-Hong eMa Xia-Chun eLi Jia-Yu eZhang Hai-Rong eShi Wei eWei Wei eWei Dan-Ju eLuo Qun eWang Jian-Zhi eWang Gong-Ping eLiu Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic mice Frontiers in Aging Neuroscience Alzheimer Disease Memory tau hyperphosphorylation inhibitor-2 of protein phosphatase-2A glycogen synthase kinase 3β |
| title | Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic mice |
| title_full | Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic mice |
| title_fullStr | Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic mice |
| title_full_unstemmed | Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic mice |
| title_short | Silencing I2PP2A rescues tau pathologies and memory deficits through rescuing PP2A and inhibiting GSK-3β signaling in human tau transgenic mice |
| title_sort | silencing i2pp2a rescues tau pathologies and memory deficits through rescuing pp2a and inhibiting gsk 3β signaling in human tau transgenic mice |
| topic | Alzheimer Disease Memory tau hyperphosphorylation inhibitor-2 of protein phosphatase-2A glycogen synthase kinase 3β |
| url | http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00123/full |
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