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.

Keywords: Alzheimer’s disease; FPN1; GPX4; ferroptosis; hepcidin; iron; iron chelator; lipid peroxidation.

FIGURE 1

The iron regulation in neuron and the mechanism of ferroptosis in AD. Iron is uptaken by neurons via holo-Tf/TfR1 complex or DMT1/PrPC-dependent manners. PrPC reduce Fe³⁺ to Fe²⁺ and DMT1 transport Fe²⁺ into neurons. Tf carrying Fe³⁺ forms a complex with TfR1, and enters neurons via clathrin-mediated endocytosis. Fe³⁺ detaches from Tf and then is reduced by STEAP3. Fe²⁺ is pumped to cytoplasm by DMT1, and is stored in ferritin in the form of Fe³⁺ when overload. In some conditions, ferritin undergoes autophagy by binding with NCOA4, releasing iron and subsequently leading to lethal iron levels and ferroptosis. Elevated irons could be excreted by FPN1/Cp or FPN1/Heph, with the assistance of APP, which is transported to stabilize FPN1 by soluble tau protein. Aging, inflammation, and oxidative stress could dysregulate the iron transport proteins and cause iron retention. When overload, iron could upregulates the expressions of ferritin, FPN1, and APP by IRP-IRE interactions, while suppresses the normal function of furin, leading to the upregulation of β-secretase and thus accelerating Aβ deposition. When xCT or GSH decreases in the neurons under some states, the decreased GPX4 cannot exert the function of anti-lipid peroxidation. After Fenton reaction or ALOX-catalyzed process, PUFA-OOH can accumulate to a lethal level to trigger ferroptosis, which could be responsible for the tau hyperphosphorylation, Aβ formation and neuronal loss.