Evidence of Redox-Active Iron Formation Following Aggregation of Ferrihydrite and the Alzheimer’s Disease Peptide β-Amyloid

Everett, James; Céspedes, Eva; Shelford, L. R.; Exley, Christopher; Collingwood, Joanna F.; Dobson, Jon; Laan, G. van der; Jenkins, Catherine; Arenholz, Elke; Telling, Neil D.

doi:10.1021/ic402406g

Cited by 56 publications

(73 citation statements)

References 48 publications

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“…However, several research teams have produced preclinical data demonstrating that prolonged association of Fe(III) with Aβ leads to the reduction of the former and increased levels of redox-active Fe(II) [355,356]. These findings have been recently reproduced in vivo in cortical tissue of AD transgenic mice [357].…”

Section: Effect Of Elevated Fe(iii) and Fe(ii) On Amyloid Plaque Formmentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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Section: Effect Of Elevated Fe(iii) and Fe(ii) On Amyloid Plaque Formmentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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“…Iron may upregulate amyloid precursor protein expression; it can also bind to amyloid formations and facilitate their fibrillation. On the other hand, Abeta is capable of reducing ferrihydrite to ferrous ion [144,145].…”

Section: Parkinson's and Alzheimer's Diseasesmentioning

confidence: 99%

Iron chelation in the treatment of neurodegenerative diseases

Dušek

Schneider

Aaseth

2016

Journal of Trace Elements in Medicine and Biology

106

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a b s t r a c tDisturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson's disease.

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“…However, the questions can become more subtle when we consider underlying mechanisms of iron-mediated toxicity. Some instances of tissue iron overload may be a consequence of impaired bioavailability (Rouault, 2013; Visanji et al, 2013), and under certain circumstances the colocalization of iron and species with, for example, reductase potential like Aβ 42 (Khan et al, 2006) or α-synuclein (Davies et al, 2011), may be a more significant contributing factor to oxidative stress damage than tissue iron concentration in its own right (Gallagher et al, 2012; Everett et al, 2014a). As SXRF may be used non-destructively, there is plenty of scope to correlate SXRF iron maps with other parameters relevant to iron-mediated toxicity, and to probe the oxidation state and mineral form of iron within SXRF maps by techniques such as XANES (Collingwood et al, 2005a; Bacquart et al, 2007).…”

Section: Xas: Looking At the Oxidation State Of Iron And Its Local Enmentioning

confidence: 99%

“…The reductase behavior of the Aβ and α-synuclein peptides has been shown in vitro (Khan et al, 2006; Davies et al, 2011). The chemical reduction of ferrihydrite (iron oxide) particles by Aβ 42 has also now been demonstrated in vitro (Everett et al, 2014a). The contribution of synchrotron X-ray analysis to such studies, and to understanding fundamental structural and conformational properties of the peptides, will be considered here.…”

Section: Introductionmentioning

confidence: 99%

“…Aberrant peptide aggregation leads to the formation of pathological hallmarks of neurodegenerative disorders such as the beta amyloid (Aβ)-rich plaques in AD, and the alpha (α-)synuclein-rich Lewy bodies in PD. Iron has long been implicated in mechanisms of toxicity associated with aberrant peptide aggregation (Rottkamp et al, 2001), although work to determine a precise role for iron is ongoing (House et al, 2004; Everett et al, 2014a). The reductase behavior of the Aβ and α-synuclein peptides has been shown in vitro (Khan et al, 2006; Davies et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light

Collingwood¹,

Davidson²

2014

Front. Pharmacol.

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There is evidence for iron dysregulation in many forms of disease, including a broad spectrum of neurodegenerative disorders. In order to advance our understanding of the pathophysiological role of iron, it is helpful to be able to determine in detail the distribution of iron as it relates to metabolites, proteins, cells, and tissues, the chemical state and local environment of iron, and its relationship with other metal elements. Synchrotron light sources, providing primarily X-ray beams accompanied by access to longer wavelengths such as infra-red, are an outstanding tool for multi-modal non-destructive analysis of iron in these systems. The micro- and nano-focused X-ray beams that are generated at synchrotron facilities enable measurement of iron and other transition metal elements to be performed with outstanding analytic sensitivity and specificity. Recent developments have increased the scope for methods such as X-ray fluorescence mapping to be used quantitatively rather than semi-quantitatively. Burgeoning interest, coupled with technical advances and beamline development at synchrotron facilities, has led to substantial improvements in resources and methodologies in the field over the past decade. In this paper we will consider how the field has evolved with regard to the study of iron in proteins, cells, and brain tissue, and identify challenges in sample preparation and analysis. Selected examples will be used to illustrate the contribution, and future potential, of synchrotron X-ray analysis for the characterization of iron in model systems exhibiting iron dysregulation, and for human cases of neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis.

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Evidence of Redox-Active Iron Formation Following Aggregation of Ferrihydrite and the Alzheimer’s Disease Peptide β-Amyloid

Cited by 56 publications

References 48 publications

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Iron chelation in the treatment of neurodegenerative diseases

The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light

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