Using multiscale and correlative spectromicroscopy to explore the metallomics of neurodegenerative disorders

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Multiscale and Correlative Microscopy Approaches to Microanalysis and Spectroscopy
Professor Joanna Collingwood (1)
1. University of Warwick

Synchrotron, x-ray, spectromicroscopy, iron, copper, brain, neurodegeneration, neuromelanin, amyloid plaque, Alzheimer's, Parkinson's.

Abstract text

Metal elements are integral to life, yet many aspects of their known form and function as biometals are unresolved, and many more are likely to be discovered. Analysis of metal elements in biological tissues presents a myriad of analytical challenges. Synchrotron x-ray spectromicroscopy offers new ways to overcome some of these challenges, and one area in which spectromicroscopy is being advanced and applied is the investigation of the role of metal elements in neurodegenerative disorders [Collingwood 2014, Lermyte 2019]. Altered patterns of metal element distributions in tissues offer scope to improve diagnosis. Meanwhile, disease-associated changes in metal element utilization offer insights into neuropathology, and even scope for treatment. 

From prior studies of post-mortem human brain, there is evidence of disrupted metal ion metabolism, as well as regional and cellular-level accumulation of certain elements in neurodegenerative disorders. These elements include demonstrably toxic non-essential metals that have entered the central nervous system (such as aluminium, mercury, and lead), essential metals in low concentrations (such as the transition metals iron and copper, typically present in parts per ten thousand to parts per million), and abundant biometals such as calcium [Collingwood 2017]. One motivation to advance analytical capabilities in this field is to better understand the role of metals in disease at regional, cellular, and subcellular levels, both to identify patterns of change that could be detected with clinical imaging methods [Finnegan 2019], and to inform the impact of metal-modifying drug treatments. Chelators are successful in treating disorders where there is clear systemic overload of a particular element (iron or copper, for example), but it is less clear what the impact of chelation will be on systems where metal ion dysregulation manifests as highly localised accumulations and/or deficiencies [Visanji 2013].

This presentation will concentrate mainly on the analysis of iron in the context of neurodegenerative disorders. There are diseases of systemic iron overload or deficiency, but in the case of neurodegenerative disorders the changes in iron regulation accompanying hallmarks of pathology may lead to changes in tissue iron concentration, to the chemical and mineral form of iron stores, and/or to changes in how other elements are regulated. In order to advance our understanding of the 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 [Everett 2020, Finnegan 2019, Lermyte 2019]. 

Synchrotron light sources provide access to intense focussed beams of x-rays, providing an outstanding tool for multi-modal non-destructive analysis of iron with outstanding analytic sensitivity and specificity [Collingwood 2014]. Burgeoning interest, coupled with technical advances and beamline development at synchrotron facilities, has led to substantial improvements in resources and methodologies in the field in recent years. The evolution of the field will be considered, both from the perspective of the measurements that can be undertaken (the complementarity of certain techniques, correlative approaches, and challenges in sample preparation and analysis), and in considering progress in describing neurodegenerative disorders.

Most recently, we have sought to identify signatures in x-ray spectra to enable mapping of organic tissue components of interest, so that these can be directly correlated with metal element distributions and their chemical properties. Examples that will be used to illustrate this approach include i) the label-free observation of neuromelanin in tandem with iron as determined by scanning transmission x-ray microscopy [Brooks 2020], and ii) the discovery of evidence for iron and copper in metallic form in amyloid protein deposits from the brains of individuals who had Alzheimer’s disease [Everett 2021].


[Brooks 2020] Brooks J, Everett J, Lermyte F, Tjhin VT, Banerjee S, O'Connor PB, Morris CM, Sadler PJ, Telling ND, Collingwood JF. Label-Free Nanoimaging of Neuromelanin in the Brain by Soft X-ray Spectromicroscopy. Angew Chem Int Ed Engl. 2020 59(29):11984-11991. doi: 10.1002/anie.202000239. Epub 2020 May 14. PMID: 32227670; PMCID: PMC7383895.

[Collingwood 2014] Collingwood J.F., Davidson M.R. The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light. Front Pharmacol. 2014 5:191. doi: 10.3389/fphar.2014.00191. PMID: 25191270; PMCID: PMC4137459

[Collingwood 2017] Collingwood J.F., Adams F. Chemical imaging analysis of the brain with X-ray methods. Spectrochimica Acta Part B : Atomic Spectroscopy 2017 130:101-118. doi:10.1016/j.sab.2017.02.013

[Everett 2020] Everett J, Brooks J, Lermyte F, O'Connor PB, Sadler PJ, Dobson J, Collingwood JF, Telling ND. Iron stored in ferritin is chemically reduced in the presence of aggregating Aβ(1-42). Sci Rep. 2020 10(1):10332. doi: 10.1038/s41598-020-67117-z. PMID: 32587293; PMCID: PMC7316746.

[Everett 2021] Everett J, Lermyte F, Brooks J, Tjendana-Tjhin V, Plascencia-Villa G, Hands-Portman I, Donnelly JM, Billimoria K, Perry G, Zhu X, Sadler PJ, O'Connor PB, Collingwood JF, Telling ND. Biogenic metallic elements in the human brain? Sci Adv. 2021 eabf6707. doi: 10.1126/sciadv.abf6707. PMID: 34108207; PMCID: PMC8189590.

[Finnegan 2019] Finnegan ME, Visanji NP, Romero-Canelon I, House E, Rajan S, Mosselmans JFW, Hazrati LN, Dobson J, Collingwood JF. Synchrotron XRF imaging of Alzheimer's disease basal ganglia reveals linear dependence of high-field magnetic resonance microscopy on tissue iron concentration. J Neurosci Methods. 2019 319:28-39. doi: 10.1016/j.jneumeth.2019.03.002. PMID: 30851339.

[Lermyte 2019] Lermyte F, Everett J, Brooks J, Bellingeri F, Billimoria K, Sadler PJ, O'Connor PB, Telling ND, Collingwood JF. Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies. Cells. 2019 8(10):1231. doi: 10.3390/cells8101231. PMID: 31658742; PMCID: PMC6829613.

[Visanji 2013] Visanji NP, Collingwood JF, Finnegan ME, Tandon A, House E, Hazrati LN. Iron deficiency in parkinsonism: region-specific iron dysregulation in Parkinson's disease and multiple system atrophy. J Parkinsons Dis. 2013 3(4):523-37. doi: 10.3233/JPD-130197. PMID: 24113558.