Cerebral Iron Deposition in Neurodegeneration

Abstract

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias

“…Thus, GLB1 has been suggested as an NBIA gene [ 49 ], although this depends on the authors. Single cases with NBIA phenotype have been reported for several genes such as REPS1 or CRAT [ 50 ], and in occasions, they are described as NBIA genes [ 51 ], or as genes to be considered NBIA genes if additional cases are reported [ 52 ].…”

Blood Analytes as Biomarkers of Mechanisms Involved in Alzheimer’s Disease Progression

“…On the other hand, Fe, ferritin and total and HDL-cholesterol were all inversely related to AD severity and were shown by the Reactome database analysis to be involved in the subpathway of small molecules and vesicle-mediated transport and to converge towards an overactivation of scavenger receptors (SRs). SRs consist of a broad family of multifunctional proteins found on the membrane of a variety of cells, including microglial cells, involved in the binding and clearance of toxic ligands [ 48 , 49 ]. This altered signal could be indicative of an increased molecule trafficking during the neuroinflammation progression [ 50 , 51 , 52 ].…”

“…As a matter of fact, based on postmortem analyses, individuals with A plaques and large Fe deposits are highly likely to develop dementia [ 56 ], possibly implicating that a tendency towards brain Fe accumulation could be a factor increasing AD susceptibility. In addition, during the onset of AD, microglial cells are believed to protect the brain by incorporating extracellular A filaments that are prone to bind several metals, such as Cu, Zn and Fe [ 49 , 57 ], until their maximum buffering capacity [ 57 ]. In this way, across years, Fe ions could increase and accumulate within the brain.…”

“…Fe can enter the cell via transferrin 1 receptor and be reduced from ferric to ferrous form via a metalloreductase in the endosome: in such a form, Fe can be stored in ferritin, or exported from the cell through ferroportin [ 56 , 58 ]. Fe accumulation with age in several brain compartments has been known for a long time, even though no satisfactory explanation has been drawn on that regard, including all the related consequences and implications [ 49 ]. Since brain Fe content increases more dramatically during neurodegenerative diseases, causing the onset of sideroptosis (ferroptosis), an Fe-dependent and lipid peroxidation-driven type of programmed cell death [ 59 ], it is likely that ferroptosis may offer an additional contribution to neurodegeneration in AD.…”

Therapeutic targeting of microglia mediated oxidative stress after neurotrauma

“…Iron combined with mitochondrial oxidative stress can cause microglia to undergo ferroptosis, an iron-dependent programmed cell death ( 71 , 72 ), or induce ferroptosis in other cells via iron dysregulation or NO release ( 73 , 74 ). Recent research from our laboratory demonstrated that iron induces ROS production in microglia and amplifies ROS of stimulated microglia ( 75 ).…”