BACKGROUND Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer's disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown. METHODS This work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation. RESULTS Levels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau. CONCLUSIONS Up-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions.

中文翻译：

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tau 寡聚物引起的突触和记忆功能障碍可通过一氧化氮级联的上调来缓解。


背景 tau 蛋白（oTau）寡聚形式的可溶性聚集体与阿尔茨海默氏病中突触可塑性和记忆力的损害有关。然而，oTau 升高引起的突触和记忆功能障碍的分子机制仍不清楚。方法 这项工作结合了生物化学、电生理学和行为技术。生化方法包括分析 cAMP 反应元件结合 (CREB) 蛋白的磷酸化，CREB ​​是一种参与记忆、组蛋白乙酰化以及立即早期基因 c-Fos 和 Arc 表达的转录因子。电生理学方法包括评估长时程增强（LTP），一种被认为是记忆形成基础的突触可塑性。行为研究调查了短期空间记忆和联想记忆。在 oTau 升高后对这些现象进行了检查。结果 记忆形成过程中，oTau 升高后，磷酸化 CREB、组蛋白 3 赖氨酸 27 乙酰化以及立即早期基因 c-Fos 和 Arc 的水平被发现降低。这些发现引导我们探索影响 CREB ​​的一氧化氮 (NO) 信号通路的各种成分的上调是否能够挽救 oTau 诱导的可塑性、记忆和 CREB ​​磷酸化损伤。 NO 水平的增加可通过激活可溶性鸟苷酸环化酶来防止 oTau 诱导的 LTP 损伤。同样，暴露于 oTau 后，cGMP 水平的升高和 cGMP 依赖性蛋白激酶 (PKG) 的刺激重新建立了正常的 LTP。通过抑制磷酸二酯酶 5 (PDE5) 来药理学抑制 cGMP 降解，挽救 oTau 诱导的 LTP 降低。 这些发现可以推断到记忆，因为 PKG 激活和 PDE5 抑制可以挽救 oTau 诱导的记忆障碍。最后，在 oTau 存在的情况下诱导记忆后，PDE5 抑制重新建立了 CREB ​​磷酸化和 cGMP 水平的正常升高。结论 通过作用于 NO 级联的药物上调 CREB ​​激活可能有益于对抗 tau 诱导的突触和记忆功能障碍。