Iron and Alzheimer’s Disease: An Update on Emerging Mechanisms

Abstract

Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron's biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This "Janus-faced" nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer's disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves "ferroptosis", a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD.

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

“…Inhibition of ferroptosis can also improve brain cell survival and neurological outcomes after hemorrhagic stroke and traumatic brain injury . Intriguingly, important features of ferroptosis, including the loss of GSH, increased ROS, and lipid peroxidation, have been observed in models of Alzheimer's disease and Parkinson's disease, suggesting a potential link between these diseases and ferroptosis . Characterizing the specific GPX4‐regulated lipid peroxidation events in diseases states—pioneered by the Kagan laboratory for asthma, acute kidney injury, and traumatic brain injury—remains an important goal for other conditions where ferroptosis is implicated.…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…Iron is the most abundant transition metal in the brain. In the CNS, iron can participate in critical functions including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, synaptic plasticity (Devos et al, 2014), and neurotransmitter synthesis and decomposition (Lane et al, 2018). The blood-brain barrier (BBB) ingests iron through transferrin on brain capillary endothelial cells, and then transports it into the cerebral cytoplasm through astrocytes or through divalent cation-binding protein (DMT1) and maintains iron an approximately saturated steady state in the brain (Belaidi and Bush, 2016), thereby maintaining the normal physiological function of the nervous system.…”

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…During past decades, a great number of studies have focused on addressing whether the abnormally increased brain iron is an initial cause for the development of neurodegeneration and neuronal death. A number of excellent reviews on the updated understanding of this question have recently been published …”

“…In several other neurodegenerative disorders including AD, PD, HD, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia, loss of iron homeostasis, oxidative stress, and mitochondrial injury have been suggested to constitute a common pathway to cell death although the pathological hallmarks of these neurodegenerative diseases vary. Currently, a key question of why iron increases abnormally in some brain regions of these diseases has not been answered.…”