Mapping and characterization of iron compounds in Alzheimer's tissue
Authors: Collingwood, Joanna | Dobson, Jon
Article Type: Research Article
Abstract: Understanding the management of iron in the brain is of great importance in the study of neurodegeneration, where regional iron overload is frequently evident. A variety of approaches have been employed, from quantifying iron in various anatomical structures, to identifying genetic risk factors related to iron metabolism, and exploring chelation approaches to tackle iron overload in neurodegenerative disease. However, the ease with which iron can change valence state ensures that it is present in vivo in a wide variety of forms, both soluble and insoluble. Here, we review recent developments in approaches to locate and identify iron compounds in neurodegenerative …tissue. In addition to complementary techniques that allow us to quantify and identify iron compounds using magnetometry, extraction, and electron microscopy, we are utilizing a powerful combined mapping/characterization approach with synchrotron X-rays. This has enabled the location and characterization of iron accumulations containing magnetite and ferritin in human Alzheimer's disease (AD) brain tissue sections in situ at micron-resolution. It is hoped that such approaches will contribute to our understanding of the role of unusual iron accumulations in disease pathogenesis, and optimise the potential to use brain iron as a clinical biomarker for early detection and diagnosis. Show more
Keywords: Iron, Alzheimer's disease, synchrotron, X-ray, ferritin, magnetite, hemosiderin, magnetometry, electron microscopy
DOI: 10.3233/JAD-2006-102-308
Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 215-222, 2006
Response to Comment on “Mapping and Characterization of Iron Compounds in Alzheimer's Tissue”
Authors: Dobson, Jon | Collingwood, Joanna F.
Article Type: Article Commentary
DOI: 10.3233/JAD-2007-11408
Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 469-470, 2007
Iron Deficiency in Parkinsonism: Region-Specific Iron Dysregulation in Parkinson's Disease and Multiple System Atrophy
Authors: Visanji, Naomi P. | Collingwood, Joanna F. | Finnegan, Mary E. | Tandon, Anurag | House, Emily | Hazrati, Lili-Naz
Article Type: Research Article
Abstract: Alpha synuclein pathology is widespread and found in diverse cell types in multiple system atrophy (MSA) as compared to Parkinson's disease (PD). The reason for this differential distribution is unknown. Regional differences in the distribution of iron are associated with neurodegenerative diseases, and here we characterize the relationship between iron homeostasis proteins and regional concentration, distribution and form of iron in MSA and PD. In PD substantia nigra, tissue iron and expression of the iron export protein ferroportin increased, while the iron storage protein ferritin expression was unchanged. In the basis pontis of MSA cases, increased total iron concentration coupled …with a disproportionate increase in ferritin in dysmorphic microglia and a reduction in ferroportin expression. This is supported by isothermal remanent magnetisation evidence consistent with elevated concentrations of ferritin-bound iron in MSA basis pontis. Conventional opinion holds that excess iron is involved in neurodegeneration. Our data support that this may be the case in PD. While region-specific changes in iron are evident in both PD and MSA, the mechanisms of iron dysregulation appear quite distinct, with a failure to export iron from the MSA basis pontis coupling with significant intracellular accumulation of ferritin iron. This pattern also occurs, to a lesser extent, in the MSA putamen. Despite the excess tissue iron, the manner of iron dysregulation in MSA is reminiscent of changes in anemia of chronic disease, and our preliminary data, coupled with the widespread pathology and involvement of multiple cell types, may evidence a deficit in bioavailabile iron. Show more
Keywords: Parkinson's disease, multiple system atrophy, iron, ferritin, inflammation, ferroportin
DOI: 10.3233/JPD-130197
Citation: Journal of Parkinson's Disease, vol. 3, no. 4, pp. 523-537, 2013
Modest Amyloid Deposition is Associated with Iron Dysregulation, Microglial Activation, and Oxidative Stress
Authors: Gallagher, Joseph J. | Finnegan, Mary E. | Grehan, Belinda | Dobson, Jon | Collingwood, Joanna F. | Lynch, Marina A.
Article Type: Research Article
Abstract: There is a well-established literature indicating a relationship between iron in brain tissue and Alzheimer's disease (AD). More recently, it has become clear that AD is associated with neuroinflammatory and oxidative changes which probably result from microglial activation. In this study, we investigated the correlative changes in microglial activation, oxidative stress, and iron dysregulation in a mouse model of AD which exhibits early-stage amyloid deposition. Microfocus X-ray absorption spectroscopy analysis of intact brain tissue sections prepared from AβPP/PS1 transgenic mice revealed the presence of magnetite, a mixed-valence iron oxide, and local elevations in iron levels in tissue associated with amyloid-β-containing …plaques. The evidence indicates that the expression of markers of microglial activation, CD11b and CD68, and astrocytic activation, GFAP, were increased, and were histochemically determined to be adjacent to amyloid-β-containing plaques. These findings support the contention that, in addition to glial activation and oxidative stress, iron dysregulation is an early event in AD pathology. Show more
Keywords: Alzheimer's disease, iron, microglia, oxidative stress, spectrometry, X-ray fluorescence
DOI: 10.3233/JAD-2011-110614
Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 147-161, 2012
Copper Abolishes the β-Sheet Secondary Structure of Preformed Amyloid Fibrils of Amyloid-β 42
Authors: House, Emily | Mold, Matthew | Collingwood, Joanna | Baldwin, Alex | Goodwin, Steven | Exley, Christopher
Article Type: Research Article
Abstract: The observation of the co-deposition of metals and amyloid-β42 (Aβ42 ) in brain tissue in Alzheimer's disease prompted myriad investigations into the role played by metals in the precipitation of this peptide. Copper is bound by monomeric Aβ42 and upon precipitation of the copper-peptide complex thereby prevents Aβ42 from adopting a β-sheet secondary structure. Copper is also bound by β-sheet conformers of Aβ42 , and herein we have investigated how this interaction affects the conformation of the precipitated peptide. Copper significantly reduced the thioflavin T fluorescence of aged, fibrillar Aβ42 with, for example, a 20-fold excess of the metal resulting …in a ca 90% reduction in thioflavin T fluorescence. Transmission electron microscopy showed that copper significantly reduced the quantities of amyloid fibrils while Congo red staining and polarized light demonstrated a copper-induced abolition of apple-green birefringence. Microscopy under cross-polarized light also revealed the first observation of spherulites of Aβ42 . The size and appearance of these amyloid structures were found to be very similar to spherulites identified in Alzheimer's disease tissue. The combined results of these complementary methods strongly suggested that copper abolished the β-sheet secondary structure of pre-formed, aged amyloid fibrils of Aβ42 . Copper may protect against the presence of β-sheets of Aβ42 in vivo, and its binding by fibrillar Aβ42 could have implications for Alzheimer's disease therapy. Show more
Keywords: Aluminum, Alzheimer's disease, amyloid, Aβ42, β-sheet, Congo red, copper, spherulites, TEM, thioflavin T
DOI: 10.3233/JAD-2009-1235
Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 811-817, 2009
Spherulites of Amyloid-β 42 In Vitro and in Alzheimer's Disease
Authors: Exley, Christopher | House, Emily | Collingwood, Joanna F. | Davidson, Mark R. | Cannon, Danielle | Donald, Athene M.
Article Type: Research Article
Abstract: Several amyloidogenic proteins including insulin, β-lactoglobulin, and albumin form spherulites in vitro under non-physiological conditions. These micrometer-sized, roughly spherical structures are composed of ordered arrays of amyloid fibrils in radial arrangements which, characteristically, show a typical Maltese cross pattern of light extinction under the polarizing microscope. The physiological significance of amyloid spherulites is unknown though in Alzheimer's disease, senile plaques composed primarily of β sheets of amyloid-β (Aβ)42 have, very occasionally, been shown to give a Maltese cross pattern of light extinction under crossed polarizers. Herein we describe the first observation of the formation in vitro of spherulites of Aβ42 …. They were formed under near-physiological conditions in which the β sheet conformation of pre-formed aggregates of Aβ42 had been abolished following the addition of an excess of copper. Incubation of these preparations at 37°C for up to 9 months resulted in the formation of globular structures, 5–20 μm in diameter, which exhibited a Maltese cross pattern of light extinction typical of spherulites. Near-identical spherulitic structures were also observed in abundance in 30 μm thick sections of Alzheimer's disease brain tissue. Synchrotron x-ray fluorescence showed that the location of these spherulites in AD tissue coincided with locally elevated concentrations of tissue copper. The formation in vitro of spherulites of Aβ42 which morphologically appeared analogous to spherulitic structures observed in vivo strongly supports the hypothesis that spherulites and senile plaques in AD tissue are one and the same structures and that their ultimate formation may involve copper. Show more
Keywords: Aβ42, Alzheimer's disease, amyloid, copper, senile or neuritic plaque, spherulite
DOI: 10.3233/JAD-2010-091630
Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1159-1165, 2010
Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Aβ 42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease
Authors: House, Emily | Collingwood, Joanna | Khan, Ayesha | Korchazkina, Olga | Berthon, Guy | Exley, Christopher
Article Type: Research Article
Abstract: Metals are found associated with β-pleated sheets of Aβ42 in vivo and may be involved in their formation. Metal chelation has been proposed as a therapy for Alzheimer's disease on the basis that it may safely dissolve precipitated Aβ peptides. We have followed fibrillisation of Aβ42 in the presence of an additional metal ion (Al(III), Fe(III), Zn(II), Cu(II)) over a period of 32 weeks and we have investigated the dissolution of these aged peptide aggregates in the presence of both desferrioxamine (DFO) and ethylenediaminetetraacetic acid (EDTA). Aβ42 either alone or in the presence of Al(III) or Fe(III) formed β-pleated sheets …of plaque-like amyloids which were dissolved upon incubation with either chelator. Zn(II) inhibited whilst Cu(II) prevented the formation of β-pleated sheets of Aβ42 and neither of these influences were affected by incubation of the aged peptide aggregates with either DFO or EDTA. Freshly prepared solutions of Aβ42 either alone or in the presence of added Al(III) or Fe(III) did not form β-pleated amyloid in the presence of DFO when incubated for up to 8 weeks. EDTA did not prevent β-pleated amyloid formation in the same treatments and promoted β-pleated amyloid formation in the presence of either Zn(II) or Cu(II). The presence of significant concentrations of Al(III) and Fe(III) as contaminants of 'Aβ42 only' preparations suggested that both of these metals were involved in either triggering the formation or stabilising the structure of β-pleated amyloid. If the formation of such amyloid is critical to the aetiology of AD then the chelation of Al(III) and Fe(III) may prove to be a protective mechanism whilst the chelation of Cu(II) and Zn(II) without also chelating Al(III) and Fe(III) might actually exacerbate the condition. Show more
Keywords: Aβ42, amyloid, aluminium, iron, zinc, copper, chelation, Alzheimer's disease
DOI: 10.3233/JAD-2004-6310
Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 291-301, 2004
Three-Dimensional Tomographic Imaging and Characterization of Iron Compounds within Alzheimer's Plaque Core Material
Authors: Collingwood, Joanna F. | Chong, Ryan K. K. | Kasama, Takeshi | Cervera-Gontard, Lionel | Dunin-Borkowski, Rafal E. | Perry, George | Pósfai, Mihály | Siedlak, Sandra L. | Simpson, Edward T. | Smith, Mark A. | Dobson, Jon
Article Type: Research Article
Abstract: Although it has been known for over 50 years that abnormal concentrations of iron are associated with virtually all neurodegenerative diseases, including Alzheimer's disease, its origin, nature and role have remained a mystery. Here, we use high-resolution transmission electron microscopy (HR-TEM), energy dispersive X-ray (EDX) spectroscopy and electron energy-loss spectroscopy (EELS), electron tomography, and electron diffraction to image and characterize iron-rich plaque core material – a hallmark of Alzheimer's disease pathology – in three dimensions. In these cores, we unequivocally identify biogenic magnetite and/or maghemite as the dominant iron compound. Our results provide an indication that abnormal iron biomineralization processes …are likely occurring within the plaque or the surrounding diseased tissue and may play a role in aberrant peptide aggregation. The size distribution of the magnetite cores implies formation from a ferritin precursor, implicating a malfunction of the primary iron storage protein in the brain. Show more
Keywords: Alzheimer's disease, amyloid, electron microscopy, ferritin, imaging, iron, magnetite, senile plaque core, tomography
DOI: 10.3233/JAD-2008-14211
Citation: Journal of Alzheimer's Disease, vol. 14, no. 2, pp. 235-245, 2008