The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer’s disease
Alzheimer’s disease (AD) is a severe neurodegenerative disease characterized mainly by the formation of amyloid beta (Aβ) plaques and abnormal phosphorylation of tau. In recent years, an imbalance in iron homeostasis has been recognized to play a key role in the pathological process of AD. Abnormal...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1540019/full |
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| author | Fei-Xiang Liu Fei-Xiang Liu Fei-Xiang Liu Shun-Zhi Yang Kai-Kai Shi Ding-Ming Li Jia-bin Song Lu Sun Xue Dang Jin-Yao Li Zi-qi Deng Min Zhao Min Zhao Yan-Chen Feng Yan-Chen Feng |
| author_facet | Fei-Xiang Liu Fei-Xiang Liu Fei-Xiang Liu Shun-Zhi Yang Kai-Kai Shi Ding-Ming Li Jia-bin Song Lu Sun Xue Dang Jin-Yao Li Zi-qi Deng Min Zhao Min Zhao Yan-Chen Feng Yan-Chen Feng |
| author_sort | Fei-Xiang Liu |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is a severe neurodegenerative disease characterized mainly by the formation of amyloid beta (Aβ) plaques and abnormal phosphorylation of tau. In recent years, an imbalance in iron homeostasis has been recognized to play a key role in the pathological process of AD. Abnormal iron accumulation can activate various kinases such as glycogen synthase kinase-3β, cyclin-dependent kinase 5, and mitogen-activated protein kinase, leading to abnormal phosphorylation of tau and amyloid precursor protein, and accelerating the formation of Aβ plaques and neurofibrillary tangles. In addition, iron-mediated oxidative stress not only triggers neuronal damage, but also exacerbates neuronal dysfunction by altering the phosphorylation of N-methyl-D-aspartate receptors and γ-aminobutyric acid type A receptors. Iron accumulation also affects the phosphorylation status of tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, interfering with the dopamine signaling pathway. On the other hand, iron affects iron transport and metabolism in the brain by regulating the phosphorylation of transferrin, further disrupting iron homeostasis. Therapeutic strategies targeting iron metabolism show promise by reducing iron accumulation, inhibiting oxidative stress, and reducing abnormal phosphorylation of key proteins. This article reviews the molecular mechanisms of phosphorylation modifications mediated by iron homeostasis imbalance in AD, and discusses the potential of interventions that regulate iron metabolism and related signaling pathways, providing a new theoretical basis for the treatment of AD. |
| format | Article |
| id | doaj-art-85a647e07e0949ca8a228915d9282efb |
| institution | DOAJ |
| issn | 1663-4365 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj-art-85a647e07e0949ca8a228915d9282efb2025-08-20T03:11:03ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652025-02-011710.3389/fnagi.2025.15400191540019The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer’s diseaseFei-Xiang Liu0Fei-Xiang Liu1Fei-Xiang Liu2Shun-Zhi Yang3Kai-Kai Shi4Ding-Ming Li5Jia-bin Song6Lu Sun7Xue Dang8Jin-Yao Li9Zi-qi Deng10Min Zhao11Min Zhao12Yan-Chen Feng13Yan-Chen Feng14Department of Neuropsychiatry and Psychology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, ChinaHospital of Encephalopathy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, ChinaThe First Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou, ChinaSchool of Medicine, Henan University of Chinese Medicine, Zhengzhou, ChinaSchool of Medicine, Henan University of Chinese Medicine, Zhengzhou, ChinaSchool of Medicine, Henan University of Chinese Medicine, Zhengzhou, ChinaCollege of Acupuncture, Moxibustion and Tuina, Henan University of Chinese Medicine, Zhengzhou, ChinaThe First Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou, ChinaTraditional Chinese Medicine (Zhong Jing) School, Henan University of Chinese Medicine, Zhengzhou, ChinaTraditional Chinese Medicine (Zhong Jing) School, Henan University of Chinese Medicine, Zhengzhou, ChinaSchool of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, ChinaHospital of Encephalopathy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, ChinaThe First Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou, ChinaHospital of Encephalopathy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, ChinaThe First Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou, ChinaAlzheimer’s disease (AD) is a severe neurodegenerative disease characterized mainly by the formation of amyloid beta (Aβ) plaques and abnormal phosphorylation of tau. In recent years, an imbalance in iron homeostasis has been recognized to play a key role in the pathological process of AD. Abnormal iron accumulation can activate various kinases such as glycogen synthase kinase-3β, cyclin-dependent kinase 5, and mitogen-activated protein kinase, leading to abnormal phosphorylation of tau and amyloid precursor protein, and accelerating the formation of Aβ plaques and neurofibrillary tangles. In addition, iron-mediated oxidative stress not only triggers neuronal damage, but also exacerbates neuronal dysfunction by altering the phosphorylation of N-methyl-D-aspartate receptors and γ-aminobutyric acid type A receptors. Iron accumulation also affects the phosphorylation status of tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, interfering with the dopamine signaling pathway. On the other hand, iron affects iron transport and metabolism in the brain by regulating the phosphorylation of transferrin, further disrupting iron homeostasis. Therapeutic strategies targeting iron metabolism show promise by reducing iron accumulation, inhibiting oxidative stress, and reducing abnormal phosphorylation of key proteins. This article reviews the molecular mechanisms of phosphorylation modifications mediated by iron homeostasis imbalance in AD, and discusses the potential of interventions that regulate iron metabolism and related signaling pathways, providing a new theoretical basis for the treatment of AD.https://www.frontiersin.org/articles/10.3389/fnagi.2025.1540019/fullironiron metabolismprotein phosphorylationAlzheimer’s diseasepost-translational modification of proteins |
| spellingShingle | Fei-Xiang Liu Fei-Xiang Liu Fei-Xiang Liu Shun-Zhi Yang Kai-Kai Shi Ding-Ming Li Jia-bin Song Lu Sun Xue Dang Jin-Yao Li Zi-qi Deng Min Zhao Min Zhao Yan-Chen Feng Yan-Chen Feng The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer’s disease Frontiers in Aging Neuroscience iron iron metabolism protein phosphorylation Alzheimer’s disease post-translational modification of proteins |
| title | The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer’s disease |
| title_full | The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer’s disease |
| title_fullStr | The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer’s disease |
| title_full_unstemmed | The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer’s disease |
| title_short | The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer’s disease |
| title_sort | role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of alzheimer s disease |
| topic | iron iron metabolism protein phosphorylation Alzheimer’s disease post-translational modification of proteins |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1540019/full |
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