Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau
Age is the largest risk factor for Alzheimer’s disease (AD) and contributes to cognitive impairment in otherwise healthy individuals. Thus, it is critical that we better understand the risk aging presents to vulnerable regions of the brain and carefully design therapeutics to address those effects....
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Aging Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2020.576723/full |
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| author | Shannon N. Leslie Shannon N. Leslie Dibyadeep Datta Kyle R. Christensen Christopher H. van Dyck Christopher H. van Dyck Christopher H. van Dyck Amy F. T. Arnsten Angus C. Nairn |
| author_facet | Shannon N. Leslie Shannon N. Leslie Dibyadeep Datta Kyle R. Christensen Christopher H. van Dyck Christopher H. van Dyck Christopher H. van Dyck Amy F. T. Arnsten Angus C. Nairn |
| author_sort | Shannon N. Leslie |
| collection | DOAJ |
| description | Age is the largest risk factor for Alzheimer’s disease (AD) and contributes to cognitive impairment in otherwise healthy individuals. Thus, it is critical that we better understand the risk aging presents to vulnerable regions of the brain and carefully design therapeutics to address those effects. In this study we examined age-related changes in cAMP-regulatory protein, phosphodiesterase 4D (PDE4D). Inhibition of PDE4D is currently under investigation as a therapeutic target for AD based on memory-enhancing effects in rodent hippocampus. Therefore, it is important to understand the role of PDE4D in brain regions particularly vulnerable to disease such as the frontal association cortex (FC), where cAMP signaling can impair working memory via opening of potassium channels. We found that PDE4D protein level was decreased in the FC of both moderately and extremely aged rats, and that PDE4D level was correlated with performance on a FC-dependent working memory task. In extremely aged rats, PDE4D was also inversely correlated with levels of phosphorylated tau at serine 214 (S214), a site phosphorylated by protein kinase A. In vitro studies of the PDE4D inhibitor, GEBR-7b, further illustrated that inhibition of PDE4D activity enhanced phosphorylation of tau. pS214-tau phosphorylation is associated with early AD tau pathology, promotes tau dissociation from microtubules and primes subsequent tau hyperphosphorylation at other critical AD-related sites. Age-related loss of PDE4D may thus contribute to the specific vulnerability of the FC to degeneration in AD, and play a critical role in normal cAMP regulation, cautioning against the use of pan-PDE4D inhibitors as therapeutics. |
| first_indexed | 2024-12-12T19:42:40Z |
| format | Article |
| id | doaj.art-79e9bc0a54fd40069af7bd4e5a5abb26 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-12T19:42:40Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-79e9bc0a54fd40069af7bd4e5a5abb262022-12-22T00:14:09ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652020-10-011210.3389/fnagi.2020.576723576723Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of TauShannon N. Leslie0Shannon N. Leslie1Dibyadeep Datta2Kyle R. Christensen3Christopher H. van Dyck4Christopher H. van Dyck5Christopher H. van Dyck6Amy F. T. Arnsten7Angus C. Nairn8Interdepartmental Neuroscience Program, Yale University, School of Medicine, New Haven, CT, United StatesDepartment of Psychiatry, Yale University, School of Medicine, New Haven, CT, United StatesDepartment of Neuroscience, Yale University, School of Medicine, New Haven, CT, United StatesDepartment of Psychiatry, Yale University, School of Medicine, New Haven, CT, United StatesDepartment of Psychiatry, Yale University, School of Medicine, New Haven, CT, United StatesDepartment of Neuroscience, Yale University, School of Medicine, New Haven, CT, United StatesDepartment of Neurology, Yale University, School of Medicine, New Haven, CT, United StatesDepartment of Neuroscience, Yale University, School of Medicine, New Haven, CT, United StatesDepartment of Psychiatry, Yale University, School of Medicine, New Haven, CT, United StatesAge is the largest risk factor for Alzheimer’s disease (AD) and contributes to cognitive impairment in otherwise healthy individuals. Thus, it is critical that we better understand the risk aging presents to vulnerable regions of the brain and carefully design therapeutics to address those effects. In this study we examined age-related changes in cAMP-regulatory protein, phosphodiesterase 4D (PDE4D). Inhibition of PDE4D is currently under investigation as a therapeutic target for AD based on memory-enhancing effects in rodent hippocampus. Therefore, it is important to understand the role of PDE4D in brain regions particularly vulnerable to disease such as the frontal association cortex (FC), where cAMP signaling can impair working memory via opening of potassium channels. We found that PDE4D protein level was decreased in the FC of both moderately and extremely aged rats, and that PDE4D level was correlated with performance on a FC-dependent working memory task. In extremely aged rats, PDE4D was also inversely correlated with levels of phosphorylated tau at serine 214 (S214), a site phosphorylated by protein kinase A. In vitro studies of the PDE4D inhibitor, GEBR-7b, further illustrated that inhibition of PDE4D activity enhanced phosphorylation of tau. pS214-tau phosphorylation is associated with early AD tau pathology, promotes tau dissociation from microtubules and primes subsequent tau hyperphosphorylation at other critical AD-related sites. Age-related loss of PDE4D may thus contribute to the specific vulnerability of the FC to degeneration in AD, and play a critical role in normal cAMP regulation, cautioning against the use of pan-PDE4D inhibitors as therapeutics.https://www.frontiersin.org/articles/10.3389/fnagi.2020.576723/fulltauworking memoryPDE4DagingAlzheimer’s disease |
| spellingShingle | Shannon N. Leslie Shannon N. Leslie Dibyadeep Datta Kyle R. Christensen Christopher H. van Dyck Christopher H. van Dyck Christopher H. van Dyck Amy F. T. Arnsten Angus C. Nairn Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau Frontiers in Aging Neuroscience tau working memory PDE4D aging Alzheimer’s disease |
| title | Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau |
| title_full | Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau |
| title_fullStr | Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau |
| title_full_unstemmed | Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau |
| title_short | Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau |
| title_sort | phosphodiesterase pde4d is decreased in frontal cortex of aged rats and positively correlated with working memory performance and inversely correlated with pka phosphorylation of tau |
| topic | tau working memory PDE4D aging Alzheimer’s disease |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2020.576723/full |
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