Pterosin D-activated protein kinase A mitigates Alzheimer's disease in 5xFAD mice.

IF 3.4 3区 医学 Q2 NEUROSCIENCES
Ha Na Kim, Won Hee Jang, Nam Sook Kang, Sungsub Kim, Kwang-Eun Choi, Anand Balupuri, Seong Su Hong, Yun-Hyeok Choi, Eun-Jae Lee, Lynkyung Choi, Jae-Young Koh, Gil Hong Park
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Abstract

BackgroundProtein kinase A (PKA) is a key activator of cAMP response element-binding protein signaling; it plays a pivotal role in cognition, memory, and adult neurogenesis. Phosphodiesterase (PDE) inhibitors that indirectly activate PKA through cAMP are promising candidates for Alzheimer's disease (AD) therapeutics.ObjectiveWe examined whether pterosins bind directly to PKA as activators and enhance cognition and memory.MethodsWe investigated PKA phosphorylation and performed in silico docking analysis using the cAMP-binding domains (CBD1, CBD2) of bovine PKA. Our focus was on exploring the effects of oral pterosin D on learning and memory in a 5xFAD mouse model of AD.ResultsWe demonstrated that C3-hydroxylated pterosins directly activated PKA in neuronal cells but not in astrocytes and did not affect intracellular cAMP levels or inhibit PDE. In silico modeling implied that C3-hydroxylated pterosins fitted the CBD of PKA. Pterosins enhanced long-term potentiation mossy fiber-CA1 in the mouse hippocampus without affecting normal synaptic transmission. Pterosins more potently accelerate neuronal proliferation and neurite outgrowth in primary mouse cortical neurons than dibutyryl-cAMP does. Pterosin D significantly restored cognition and memory in 5xFAD mice on the Morris water maze.ConclusionsC3-hydroxylated pterosins, as activators of PKA, have substantial potential as disease-modifying/-slowing therapeutic agent for AD.

翼鸟色素d活化蛋白激酶A减轻5xFAD小鼠的阿尔茨海默病。
蛋白激酶A (PKA)是cAMP反应元件结合蛋白信号通路的关键激活因子;它在认知、记忆和成人神经发生中起着关键作用。通过cAMP间接激活PKA的磷酸二酯酶(PDE)抑制剂是阿尔茨海默病(AD)治疗的有希望的候选者。目的探讨紫红素是否作为激活剂与PKA直接结合,增强认知和记忆能力。方法利用牛PKA的camp结合域(CBD1、CBD2)对PKA的磷酸化进行硅对接分析。我们的重点是探讨口服紫花色素D对5xFAD AD小鼠模型学习和记忆的影响。结果c3羟基化翼鸟蛋白直接激活神经元细胞中的PKA,而不激活星形胶质细胞中的PKA,并且不影响细胞内cAMP水平或抑制PDE。计算机模拟表明,c3 -羟基化的翼红素与PKA的CBD相匹配。紫菀素增强小鼠海马长时程增强苔藓纤维- ca1,但不影响正常的突触传递。翼紫红素比二丁基camp更能促进小鼠皮层原代神经元的神经元增殖和神经突生长。紫红素D可显著恢复5xFAD小鼠Morris水迷宫的认知和记忆功能。结论sc3 -羟基化翼白蛋白作为PKA的激活剂,有很大的潜力作为AD的疾病改善/减缓治疗药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Alzheimer's Disease
Journal of Alzheimer's Disease 医学-神经科学
CiteScore
6.40
自引率
7.50%
发文量
1327
审稿时长
2 months
期刊介绍: The Journal of Alzheimer''s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer''s disease. The journal publishes research reports, reviews, short communications, hypotheses, ethics reviews, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer''s disease.
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