Iron and Targeted Iron Therapy in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. β-amyloid plaque (Aβ) deposition and hyperphosphorylated tau, as well as dysregulated energy metabolism in the brain, are key factors in the progression of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, which is closely correlated with the clinical symptoms of AD; therefore, understanding the role of brain iron accumulation in the major pathological aspects of AD is critical for its treatment. This review discusses the main mechanisms and recent advances in the involvement of iron in the above pathological processes, including in iron-induced oxidative stress-dependent and non-dependent directions, summarizes the hypothesis that the iron-induced dysregulation of energy metabolism may be an initiating factor for AD, based on the available evidence, and further discusses the therapeutic perspectives of targeting iron.

Keywords: Alzheimer’s disease; ferroptosis; hyperphosphorylated tau; insulin resistance; iron; iron chelators; β-amyloid plaque.

Figure 1

Mechanisms of cellular and mitochondrial iron transport. Extracellular Fe³⁺ enters the cell via Tf/TfR1 and is reduced to Fe²⁺ by STEAP3 in endosomes and stored in LIP and FT, and excess iron is released to the outside of the cell via FPN1. Mitochondria are important organelles in the regulation of iron homeostasis, and Fe²⁺ enters mitochondria via Mfrn1/2 to participate in the synthesis of iron-sulfur clusters and heme, which affects the energy status of mitochondria, and the “kiss and run” pathway may be another potential mechanism of iron entry into mitochondria. By Figdraw (https://www.figdraw.com).

Figure 2

Iron is involved in the formation of the main pathological mechanisms of AD through a variety of pathways. Iron induces the development of IR and causes impaired cellular energy utilization and oxidative stress; iron increases the extracellular deposition of Aβ and lipid peroxidation levels by promoting APP expression and aberrant cleavage processes; iron promotes the hyperphosphorylation and aggregation of tua, the formation of NFTs, and the promotion of lipid peroxidation; and the above, combined with the accumulation of iron that occurs in the cell, ultimately causes ferroptosis in neurons. By Figdraw (https://www.figdraw.com).

Figure 3

Encapsulation of iron chelators in appropriate NPs, relying on the BBB permeability possessed by NPs, will help to achieve targeted treatment of CNS iron accumulation. By Figdraw (https://www.figdraw.com).