Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1
Alzheimer’s disease (AD) is reportedly associated with the accumulation of calcium ions (Ca2+), and this accumulation is responsible for the phosphorylation of tau. Although several lines of evidence demonstrate the above phenomenon, the inherent mechanisms remain unknown. Using APP/PS1 Tg mice and...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnagi.2019.00108/full |
| _version_ | 1818519507703955456 |
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| author | Long-Long Cao Pei-Pei Guan Yun-Yue Liang Xue-Shi Huang Pu Wang |
| author_facet | Long-Long Cao Pei-Pei Guan Yun-Yue Liang Xue-Shi Huang Pu Wang |
| author_sort | Long-Long Cao |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is reportedly associated with the accumulation of calcium ions (Ca2+), and this accumulation is responsible for the phosphorylation of tau. Although several lines of evidence demonstrate the above phenomenon, the inherent mechanisms remain unknown. Using APP/PS1 Tg mice and neuroblastoma (N)2a cells as in vivo and in vitro experimental models, we observed that Ca2+ stimulated the phosphorylation of tau by activating microsomal PGE synthase 1 (mPGES1) in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, the highly accumulated Ca2+ stimulated the expression of mPGES1 and the synthesis of PGE2. Treatment with the inhibitor of Ca2+ transporter, NMDAR, attenuated the expression of mPGES1 and the production of PGE2 were attenuated in S(+)-ketamine-treated APP/PS1 Tg mice. Elevated levels of PGE2 were responsible for the hyperphosphorylation of tau in an EP-1-, EP-2-, and EP-3-dependent but not EP4-dependent cyclin-dependent kinase (Cdk) 5-activating manner. Reciprocally, the knockdown of the expression of mPGES1 ameliorated the expected cognitive decline by inhibiting the phosphorylation of tau in APP/PS1 Tg mice. Moreover, CDK5 was found to be located downstream of EP1-3 to regulate the phosphorylation of tau though the cleavage of p35 to p25. Finally, the phosphorylation of tau by Ca2+ contributed to the cognitive decline of APP/PS1 Tg mice. |
| first_indexed | 2024-12-11T01:25:07Z |
| format | Article |
| id | doaj.art-c710d0cdf2994c268bef1620594a43ec |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-11T01:25:07Z |
| publishDate | 2019-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-c710d0cdf2994c268bef1620594a43ec2022-12-22T01:25:35ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652019-05-011110.3389/fnagi.2019.00108447607Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1Long-Long CaoPei-Pei GuanYun-Yue LiangXue-Shi HuangPu WangAlzheimer’s disease (AD) is reportedly associated with the accumulation of calcium ions (Ca2+), and this accumulation is responsible for the phosphorylation of tau. Although several lines of evidence demonstrate the above phenomenon, the inherent mechanisms remain unknown. Using APP/PS1 Tg mice and neuroblastoma (N)2a cells as in vivo and in vitro experimental models, we observed that Ca2+ stimulated the phosphorylation of tau by activating microsomal PGE synthase 1 (mPGES1) in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, the highly accumulated Ca2+ stimulated the expression of mPGES1 and the synthesis of PGE2. Treatment with the inhibitor of Ca2+ transporter, NMDAR, attenuated the expression of mPGES1 and the production of PGE2 were attenuated in S(+)-ketamine-treated APP/PS1 Tg mice. Elevated levels of PGE2 were responsible for the hyperphosphorylation of tau in an EP-1-, EP-2-, and EP-3-dependent but not EP4-dependent cyclin-dependent kinase (Cdk) 5-activating manner. Reciprocally, the knockdown of the expression of mPGES1 ameliorated the expected cognitive decline by inhibiting the phosphorylation of tau in APP/PS1 Tg mice. Moreover, CDK5 was found to be located downstream of EP1-3 to regulate the phosphorylation of tau though the cleavage of p35 to p25. Finally, the phosphorylation of tau by Ca2+ contributed to the cognitive decline of APP/PS1 Tg mice.https://www.frontiersin.org/article/10.3389/fnagi.2019.00108/fullAlzheimer’s diseasemicrosomal prostaglandin E synthase 1tauprostaglandin E2EP receptors |
| spellingShingle | Long-Long Cao Pei-Pei Guan Yun-Yue Liang Xue-Shi Huang Pu Wang Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1 Frontiers in Aging Neuroscience Alzheimer’s disease microsomal prostaglandin E synthase 1 tau prostaglandin E2 EP receptors |
| title | Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1 |
| title_full | Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1 |
| title_fullStr | Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1 |
| title_full_unstemmed | Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1 |
| title_short | Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1 |
| title_sort | calcium ions stimulate the hyperphosphorylation of tau by activating microsomal prostaglandin e synthase 1 |
| topic | Alzheimer’s disease microsomal prostaglandin E synthase 1 tau prostaglandin E2 EP receptors |
| url | https://www.frontiersin.org/article/10.3389/fnagi.2019.00108/full |
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