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.
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.
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磷酸二酯酶PDE4D在老年大鼠的额叶皮层中降低，并与工作记忆性能正相关，并与TAU的PKA磷酸化成反比。
DOI：
10.3389/fnagi.2020.576723
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发表时间：
2020
影响因子：
4.8
通讯作者：
Nairn AC
中科院分区：
文献类型：
--
作者：
Leslie SN;Datta D;Christensen KR;van Dyck CH;Arnsten AFT;Nairn AC
年龄是阿尔茨海默病 (AD) 的最大危险因素，会导致其他健康个体的认知障碍。因此，我们必须更好地了解衰老给大脑脆弱区域带来的风险，并仔细设计治疗方法来解决这些影响，这一点至关重要。在这项研究中，我们检查了 cAMP 调节蛋白磷酸二酯酶 4D (PDE4D) 与年龄相关的变化。目前正在研究抑制 PDE4D 作为 AD 的治疗靶点，基于啮齿动物海马的记忆增强作用。因此，了解 PDE4D 在特别容易受到疾病影响的大脑区域中的作用非常重要，例如额叶联合皮层 (FC)，其中 cAMP 信号传导可通过打开钾通道损害工作记忆。我们发现中龄和极度老龄大鼠的 FC 中 PDE4D 蛋白水平均下降，并且 PDE4D 水平与 FC 依赖的工作记忆任务的表现相关。在极度老龄化的大鼠中，PDE4D 还与丝氨酸 214 (S214) 处的磷酸化 tau 水平呈负相关，该位点被蛋白激酶 A 磷酸化。PDE4D 抑制剂 GEBR-7b 的体外研究进一步表明，抑制 PDE4D 活性可增强 tau 的磷酸化。 pS214-tau 磷酸化与早期 AD tau 病理学相关，促进 tau 从微管解离，并引发其他关键 AD 相关位点随后的 tau 过度磷酸化。因此，与年龄相关的 PDE4D 缺失可能导致 AD 中 FC 变性的特定脆弱性，并在正常的 cAMP 调节中发挥关键作用，因此警告不要使用泛 PDE4D 抑制剂作为治疗药物。
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.
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DOI：
10.1523/jneurosci.5236-10.2011
发表时间：
2011-01-05
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Li YF;Cheng YF;Huang Y;Conti M;Wilson SP;O'Donnell JM;Zhang HT
通讯作者：
Zhang HT
影响因子：
14
作者：
通讯作者：
--
影响因子：
16.2
作者：
Ramos, BP;Birnbaum, SG;Arnsten, AFT
通讯作者：
Arnsten, AFT
DOI：
10.1016/j.bbadis.2011.08.012
发表时间：
2011-12
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Swerdlow RH
通讯作者：
Swerdlow RH
影响因子：
16.2
作者：
Arnsten AF;Wang MJ;Paspalas CD
通讯作者：
Paspalas CD