Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Abstract

Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer’s disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development.

Ketogenic diet prevents chronic sleep deprivation-induced Alzheimer’s disease by inhibiting iron dyshomeostasis and promoting repair via Sirt1/Nrf2 pathway

“…Similar to our previous study, the up-regulation of intracellular iron was reversed by KD treatment ( Wang X. et al, 2022 ). What’s more, it has been demonstrated that iron accumulation can worsen senile plaque deposition and promote tau phosphorylation ( Wang F. et al, 2022 ). More β-secretase is activated in the presence of excessive iron and then accelerating the Aβ production and amyloid deposition ( Ayton et al, 2020 ; Gleason and Bush, 2021 ).…”

Serotonin 5-HT6 Receptor Ligands and Butyrylcholinesterase Inhibitors Displaying Antioxidant Activity—Design, Synthesis and Biological Evaluation of Multifunctional Agents against Alzheimer’s Disease

“…Compounds 15 and 18 were identified in the screening as Fe 2+ ions chelators ( Figure 5 ). This might be an advantageous feature of potential anti-neurodegenerative agents considering the correlation between iron overload, inflammation and glycolysis being inherent components of AD pathogenesis [ 58 ]. Therefore, the growing number of iron-chelating compounds with potential disease-modifying efficacy and the availability of MRI and CSF biomarkers of iron load encourage a deeper exploration of this therapeutic class in AD [ 59 ].…”

New Possibilities in the Therapeutic Approach to Alzheimer’s Disease

“…Early research discovered that Alzheimer’s disease’s cognitive deterioration is directly correlated with iron excess. What is more, both APP and tau protein are connected with iron metabolism [ 20 ]. Iron participates in the creation of neurotransmitters, myelination, and antioxidant enzyme activity in the brain [ 21 ].…”