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
{"title":"翼鸟色素d活化蛋白激酶A减轻5xFAD小鼠的阿尔茨海默病。","authors":"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","doi":"10.1177/13872877251344627","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>in silico</i> 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. <i>In silico</i> 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.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"13872877251344627"},"PeriodicalIF":3.4000,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pterosin D-activated protein kinase A mitigates Alzheimer's disease in 5xFAD mice.\",\"authors\":\"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\",\"doi\":\"10.1177/13872877251344627\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <i>in silico</i> 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. <i>In silico</i> 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.</p>\",\"PeriodicalId\":14929,\"journal\":{\"name\":\"Journal of Alzheimer's Disease\",\"volume\":\" \",\"pages\":\"13872877251344627\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-06-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Alzheimer's Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/13872877251344627\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Alzheimer's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/13872877251344627","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Pterosin D-activated protein kinase A mitigates Alzheimer's disease in 5xFAD mice.
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.
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.