Iron and Alzheimer's Disease: From Pathogenesis to Therapeutic Implications

Abstract

As people age, iron deposits in different areas of the brain may impair normal cognitive function and behavior. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, and ultimately leads to cell death. There is an imbalance in iron homeostasis in Alzheimer's disease (AD). Excessive iron contributes to the deposition of β-amyloid and the formation of neurofibrillary tangles, which in turn, promotes the development of AD. Therefore, iron-targeted therapeutic strategies have become a new direction. Iron chelators, such as desferoxamine, deferiprone, deferasirox, and clioquinol, have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Given the limitations and side effects of the long-term application of traditional iron chelators, alpha-lipoic acid and lactoferrin, as self-synthesized naturally small molecules, have shown very intriguing biological activities in blocking Aβ-aggregation, tauopathy and neuronal damage. Despite a lack of evidence for any clinical benefits, the conjecture that therapeutic chelation, with a special focus on iron ions, is a valuable approach for treating AD remains widespread.

Keywords: Alzheimer’s disease; alpha-lipoic acid; chelation; iron; lactoferrin.

FIGURE 1

The schematic diagram of iron transport into cells. Part of the extracellular bivalent iron can be directly transferred into cells through DMT1. Transferrin-bound iron binds TfR1 through endocytosis to form endosomes in the cells. Due to the action of the proton pump on the endosome, trivalent iron dissociates from the Tf/TfR1 complex and is reduced to divalent iron, which enters the cytoplasm via DMT1. Part of the ferrous iron that enters the cytoplasm is used by the cell itself (such as mitochondria), and part of it is oxidized to ferrous iron by ferritin and stored. Another part is oxidized to ferric iron by the ferroxidase on the cell membrane, and the cells are exported by FPN1 and recombined with extracellular Tf.

FIGURE 2

The schematic diagram of iron participation in the deposition of Aβ plaques and tau tangles. In neurons, iron interacts with Aβ and promotes Aβ aggregation into fibrous forms. Iron can also act on the IRE site of APP mRNA, increasing the expression of endogenous APP. In addition to the interaction with Aβ, iron can also promote the phosphorylation of tau by activating the CDK5/p25 complex and GSK3β to form NFTs. At the same time, iron can also cause oxidative stress through the Fenton reaction, damaging DNA, lipids and proteins and eventually leading to cell death. The iron chelators reduce the phosphorylation of tau and inhibit the production of NFTs by inhibiting the activation of the CDK5/p25 complex and GSK3β by iron. Simultaneously, iron chelators inhibit the aggregation of Aβ monomers into toxic fibrous forms by chelating iron, delaying cell death.