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.

Keywords: MRI; NBIA; chelation; ferroptosis; iron accumulation; neurodegeneration; siderosis.

Figure 1

Common observations in healthy aging that may be accentuated in sporadic AD and PD. See text for details. Abbreviations: Aβ, amyloid-beta plaque; DA, dopamine; NE, norepinephrine; NM, neuromelanin; ROS, reactive oxygen species.

Figure 2

The neuronal xenobiotic-neuromelanin (NM) toxicity PD hypothesis. Negatively charged NM in SN attracts metal ions and positively charged xenobiotics such as basic organic amines (e.g., MPP⁺ and paraquat (PQ⁺⁺)). Such organic xenobiotics diffuse into the cytosol and/or mitochondria where they redox-cycle, oxidize DA directly or through ROS production, and subsequent Fenton chemistry/autooxidation related to increased ferrous iron in the cytosolic labile iron pool (LIP). DA oxidizes into DA-o-SQ^• and further into various DA metabolites (e.g., DA-quinone, aminochrome, 5,6-dihydroxyindole) that oligomerize into NM. NM formation is generally seen as a protective process since reactive DA metabolites are removed. However, NM Cu sequestration lowers the already low cytosolic Cu levels which could be toxic (e.g., leading to less cytosolic Cu/Zn-SOD). Xenobiotics may also exert toxicity if they somehow modify the NM structure which could alter the redox activity of bound metal ions and facilitate ROS production. Some DA metabolites, e.g., DA-o-SQ^•, DA-quinone and DOPAL (can be formed enzymatically), react with proteins including alpha-synuclein, forming toxic protein adducts (adducts may cause misfolding, and misfolded proteins tend to aggregate). If O₂^•−reacts with nitric oxide (NO^•), peroxynitrite (ONOO⁻; strong oxidant) is formed. Abbreviations: DA, dopamine; DA-o-SQ^•, DA-ortho-semiquinone radical.