The Role of Protein Phosphorylation Modifications Mediated by Iron Metabolism Regulatory Networks in the Pathogenesis of Alzheimer's Disease

Feixiang Liu ^1,2,3 Shun-Zhi Yang ⁴ Kai-Kai Shi ⁴ Ding-Ming Li ⁴ Jia-Bin Song ⁵ Lu Sun ³ Xue Dang ⁶ Jin-Yao Li ⁶ Zi-Qi Deng ⁷ Min Zhao ^2,3 Yanchen Feng ^2,3*

• ¹ Department of Neuropsychiatry and Psychology, The First Affiliated Hospital of Henan University 6 of Chinese Medicine, Zhengzhou, China
• ² Hospital of Encephalopathy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
• ³ The First Clinical Medical School, Hubei University of Chinese Medicine, Hubei, China
• ⁴ School of medicine, Henan University of Chinese Medicine, Zhengzhou, China
• ⁵ College of Acupuncture, Moxibustion and Tuina, Henan University of Chinese Medicine, Zhengzhou, China
• ⁶ Traditional Chinese Medicine (Zhong Jing) School, Henan University Of Chinese Medicine, Zhengzhou, China
• ⁷ School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan Province, China

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-Daspartate 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.