Iron in Alzheimer’s Disease: From Physiology to Disease Disabilities

Abstract

Reactive Oxygen Species (ROS) play a key role in the neurodegeneration processes. Increased oxidative stress damages lipids, proteins, and nucleic acids in brain tissue, and it is tied to the loss of biometal homeostasis. For this reason, attention has been focused on transition metals involved in several biochemical reactions producing ROS. Even though a bulk of evidence has uncovered the role of metals in the generation of the toxic pathways at the base of Alzheimer’s disease (AD), this matter has been sidelined by the advent of the Amyloid Cascade Hypothesis. However, the link between metals and AD has been investigated in the last two decades, focusing on their local accumulation in brain areas known to be critical for AD. Recent evidence revealed a relation between iron and AD, particularly in relation to its capacity to increase the risk of the disease through ferroptosis. In this review, we briefly summarize the major points characterizing the function of iron in our body and highlight why, even though it is essential for our life, we have to monitor its dysfunction, particularly if we want to control our risk of AD.

Sesamol Mitigates Chronic Iron Overload‐Induced Cognitive Impairment and Systemic Inflammation via IL‐6 and DMT1 Regulation

“…[ 17 ] Hepcidin and IL‐6 play a key role in host defense mechanisms linked to neuroinflammation. [ 60 ] Research has shown that inflammation leads to increased expression of DMT1 in neurons and increased expression of hepcidin in astrocytes and microglia. In contrast, the expression of FPN is decreased by hepcidin.…”

“…Disruption of iron homeostasis has been linked to the pathogenesis and progression of neurodegenerative mechanisms such as AD and Parkinson's disease. [58][59][60] It has been reported that iron is enriched in amyloid plaques and neurofibrillary tangles in the brains of AD patients. [23,61] Cortical iron may contribute to the deterioration of cognitive pathology and may potentially induce oxidative stress or be associated with inflammation.…”

Imbalance of Essential Metals in Traumatic Brain Injury and Its Possible Link with Disorders of Consciousness

“…Furthermore, Fe helps the immune system, cognitive, and connective tissue functionality. We absorb only as much Fe as we need, on average 1–2 mg/day (reviewed in [ 33 ]). Fe absorption is, in fact, highly regulated, and the metal is not excreted, but recycled; our body loses some Fe only by indirect processes (e.g., sloughing of skin, minor hemorrhages, and menstruation in women), but in very little amounts (about 1–2 mg/day).…”

“…Fe levels in the blood are regulated by hepcidin, a hormone that is biosynthesized in the liver. Hepcidin regulates the degradation rate of ferroportin in the enterocyte membrane, and, as a result, the rate of Fe export from the enterocyte to the blood (reviewed in [ 33 ]).…”

“…Fe, in the Fe 2+ form, catalyzes the Fenton reaction: it mediates the production of one of the most reactive ROS species, that is, the hydroxyl radical •OH, strongly increasing oxidative stress and inflammatory processes by microglia (reviewed in [ 33 ]).…”