• The relationship between iron dyshomeostasis and amyloidopathy in Alzheimer’s Disease
  • Sara Chavoshinezhad,1,* Elmira Beirami,2 Esmael Izadpanah,3
    1. Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
    2. Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
    3. Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran


  • Introduction: Alzheimer's disease (AD), a neurodegenerative condition, is defined by neurofibrillary tangles, amyloid beta (Aβ) plaques, and gradual cognitive loss. Aβ plaque typically arises by Aβ peptide buildup from the proteolytic cleavage of amyloid precursor protein (APP) in the amyloidogenic pathway. Nonetheless, amyloidogenesis is facilitated by disruption of various cellular signaling pathways. There is a growing body of evidence connecting the amount of Aβ plaque with iron buildup in the AD brain. We review new findings on iron's major pathogenic and biochemical effects on amyloidogenic pathway progression.
  • Methods: The databases Science Direct, Google Scholar, PubMed, were searched using relevant keywords such as "iron", "amyloid precursor protein", " amyloid beta", and "Alzheimer's disease" and relevant studies were retrieved from 2010–2024.
  • Results: Increased iron levels and their co-localization with Aβ plaques have been detected in the hippocampus, parietal cortex, and motor cortex of AD brains, which are highly correlated with the rate of neurodegeneration and the extent of memory loss. In addition, the frontal cortex of the AD animal models showed increased expression of DMT1, a crucial transporter of divalent metal ions, colocalizing with Aβ plaque. Iron also affects APP expression and processing to Aβ. Indeed, excessive cytosolic Fe2+ content promotes iron regulatory protein (IRP)-iron responsive element (IRE) interaction, upregulating APP expression. Furin regulates the APP-cleaving enzymes α- and β-secretase. In the presence of extra iron, furin impairment suppresses α-secretase and activates β-secretase, accelerating Aβ deposition. According to new preclinical research, deferoxamine (DFO) and deferiproneare iron chelators that decreased APP protein expression, switched APP processing to a nonamyloidogenic route, attenuated the Aβ load, and then markedly improved memory performance in AD models.
  • Conclusion: These studies provide more evidence that iron dyshomeostasis is a potential mechanism underlying amyloidogenesis and may help in evaluating the efficacy of iron chelation therapy for the treatment of AD.
  • Keywords: Alzheimer's disease, Iron, Amyloidopathy.