This is a free review from China that discusses the role of iron overload in resulting abnormal tau and other key protein phosphorylation and the development of neurofibrillary tangles typical of AD. The paper also discusses the possibilities of iron chelators in this respect. When we know how ATH434 works today on the mitochondrial level and in energy production it looks very promising that it would work also in AD, but nothing has been published in spite of experimental studies that have been done according to the annual report.

Review

Front Aging Neurosci

. 2025 Feb 25:17:1540019.

doi: 10.3389/fnagi.2025.1540019. eCollection 2025.

The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of Alzheimer's disease

Fei-Xiang 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}, Yan-Chen Feng ^{2 3}

Affiliations Expand

• PMID: 40071123

PMCID: PMC11893871 DOI: 10.3389/fnagi.2025.1540019

Abstract

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.