Iron, the endolysosomal system and neuroinflammation: a matter of balance

Bórquez, Daniel A.; Urrutia, Pamela J.; Núñez, Marco T.

doi:10.4103/1673-5374.324847

Cited by 7 publications

(5 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mitochondrial ferritin might be another source of iron sequestration as its mRNA and protein levels are increased in the temporal lobe of patients with AD [ 121 ]. Similar to our hypothesis, increased ferritin and decreased ferritinophagy have been proposed to lead to a functional deficiency of iron by sequestering iron, which in turn would impair mitochondrial function and amplify inflammation, thereby promoting aging and neurodegeneration [ 122 ].…”

Section: Resultssupporting

confidence: 78%

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

2023

View full text Add to dashboard Cite

The involvement of iron in the pathogenesis of Alzheimer’s disease (AD) may be multifaceted. Besides potentially inducing oxidative damage, the bioavailability of iron may be limited within the central nervous system, creating a functionally iron-deficient state. By comparing staining results from baseline and modified iron histochemical protocols, iron was found to be more tightly bound within cortical sections from patients with high levels of AD pathology compared to subjects with a diagnosis of something other than AD. To begin examining whether the bound iron could cause a functional iron deficiency, a protein-coding gene expression dataset of initial, middle, and advanced stages of AD from olfactory bulb tissue was analyzed for iron-related processes with an emphasis on anemia-related changes in initial AD to capture early pathogenic events. Indeed, anemia-related processes had statistically significant alterations, and the significance of these changes exceeded those for AD-related processes. Other changes in patients with initial AD included the expressions of transcripts with iron-responsive elements and for genes encoding proteins for iron transport and mitochondrial-related processes. In the latter category, there was a decreased expression for the gene encoding pitrilysin metallopeptidase 1 (PITRM1). Other studies have shown that PITRM1 has an altered activity in patients with AD and is associated with pathological changes in this disease. Analysis of a gene expression dataset from PITRM1-deficient or sufficient organoids also revealed statistically significant changes in anemia-like processes. These findings, together with supporting evidence from the literature, raise the possibility that a pathogenic mechanism of AD could be a functional deficiency of iron contributing to neurodegeneration.

show abstract

Section: Resultssupporting

confidence: 78%

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

2023

View full text Add to dashboard Cite

show abstract

“…Therefore, it is not farfetched to assume that iron—e.g. taken-up through a leaky BBB at the site of the SN and/or released from both NM and tyrosine hydroxylase (TH) in degenerating DA neurons of the SN—induces pathology resulting in neuroinflammation (Zecca et al 2008 ; Zhang et al 2013 ; Vila 2019 ; Salami et al 2021 ; Borquez et al 2022 ; Ward et al 2022 ; Liu et al 2022 ).…”

Section: Neuroinflammation In Pdmentioning

confidence: 99%

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

Riederer

Nagatsu

Youdim³

et al. 2023

J Neural Transm

View full text Add to dashboard Cite

Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of “Parkinson’s disease (PD).” The vast majority of PD subtypes and most cases of sporadic PD share Lewy bodies (LBs) as a characteristic pathological hallmark. However, the processes underlying LBs generation and its causal triggers are still unknown. ɑ-Synuclein (ɑ-syn, encoded by the SNCA gene) is a major component of LBs, and SNCA missense mutations or duplications/triplications are causal for rare hereditary forms of PD. Thus, it is imperative to study ɑ-syn protein and its pathology, including oligomerization, fibril formation, aggregation, and spreading mechanisms. Furthermore, there are synergistic effects in the underlying pathogenic mechanisms of PD, and multiple factors—contributing with different ratios—appear to be causal pathological triggers and progression factors. For example, oxidative stress, reduced antioxidative capacity, mitochondrial dysfunction, and proteasomal disturbances have each been suggested to be causal for ɑ-syn fibril formation and aggregation and to contribute to neuroinflammation and neural cell death. Aging is also a major risk factor for PD. Iron, as well as neuromelanin (NM), show age-dependent increases, and iron is significantly increased in the Parkinsonian substantia nigra (SN). Iron-induced pathological mechanisms include changes of the molecular structure of ɑ-syn. However, more recent PD research demonstrates that (i) LBs are detected not only in dopaminergic neurons and glia but in various neurotransmitter systems, (ii) sympathetic nerve fibres degenerate first, and (iii) at least in “brain-first” cases dopaminergic deficiency is evident before pathology induced by iron and NM. These recent findings support that the ɑ-syn/LBs pathology as well as iron- and NM-induced pathology in “brain-first” cases are important facts of PD pathology and via their interaction potentiate the disease process in the SN. As such, multifactorial toxic processes posted on a personal genetic risk are assumed to be causal for the neurodegenerative processes underlying PD. Differences in ratios of multiple factors and their spatiotemporal development, and the fact that common triggers of PD are hard to identify, imply the existence of several phenotypical subtypes, which is supported by arguments from both the “bottom-up/dual-hit” and “brain-first” models. Therapeutic strategies are necessary to avoid single initiation triggers leading to PD.

show abstract

“…The theory has recently been stated in the literature as the “Azalea hypothesis” [ 27 ], and essentially postulates that excessive Fe sequestration during ageing or neurodegenerative disease creates conditions of functional Fe deficiency in neurons, disrupting normal/healthy neuron function. It should be noted that this theory is not completely new, with others having previously proposed that localised or functional Fe deficiency could occur during ageing or neurodegenerative disease [ 24 , 106 – 108 ]. In support of this theory are recent transcriptomic analysis that indicate a degree of overlap in gene expression between brain tissue in the early stages of Alzheimer’s disease pathology and genes associated with anaemia [ 26 ].…”

Section: Functional Fe Deficiency During Ageing?mentioning

confidence: 99%

“…The impact from genetic manipulation of iron regulatory protein genes are motor neuron loss, which is attenuated if capacity for Fe sequestration is reduced, which provides a further link between Fe sequestration and functional Fe deficiency [ 102 ]. Inflammation has been proposed as a key pathological driver of Fe sequestration [ 106 ], and it is well established that expression of key Fe regulatory proteins DMT1, FPN1, and hepcidin are altered in response to inflammatory cytokines, promoting Fe sequestration [ 109 , 110 ]. Specifically, in response to pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and interleukins: DMT1 is upregulated in brain cells (increasing capacity for Fe accumulation), hepcidin is upregulated and FPN1 is downregulated (decreasing capacity for Fe efflux and/or transport), and ferritin expression is increased (increasing capacity for Fe storage [ 109 – 112 ].…”

Section: Functional Fe Deficiency During Ageing?mentioning

confidence: 99%

A commentary on studies of brain iron accumulation during ageing

Hackett

2024

J Biol Inorg Chem

View full text Add to dashboard Cite

Brain iron content is widely reported to increase during “ageing”, across multiple species from nematodes, rodents (mice and rats) and humans. Given the redox-active properties of iron, there has been a large research focus on iron-mediated oxidative stress as a contributor to tissue damage during natural ageing, and also as a risk factor for neurodegenerative disease. Surprisingly, however, the majority of published studies have not investigated brain iron homeostasis during the biological time period of senescence, and thus knowledge of how brain homeostasis changes during this critical stage of life largely remains unknown. This commentary examines the literature published on the topic of brain iron homeostasis during ageing, providing a critique on limitations of currently used experimental designs. The commentary also aims to highlight that although much research attention has been given to iron accumulation or iron overload as a pathological feature of ageing, there is evidence to support functional iron deficiency may exist, and this should not be overlooked in studies of ageing or neurodegenerative disease. Graphical abstract

show abstract

Iron, the endolysosomal system and neuroinflammation: a matter of balance

Cited by 7 publications

References 13 publications

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

Exploring Whether Iron Sequestration within the CNS of Patients with Alzheimer’s Disease Causes a Functional Iron Deficiency That Advances Neurodegeneration

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease

A commentary on studies of brain iron accumulation during ageing

Contact Info

Product

Resources

About