Your search for: 'author:("House, Emily")' has returned 6 results. (0.016s) Save search

Authors: House, Emily | Jones, Krista | Exley, Christopher

Article Type: Short Communication

Abstract: Recent evidence showed that amyloid-β, Aβ42 , formed spherulites in vitro and, possibly, in vivo in Alzheimer's disease brain tissue. We now confirm the presence of spherulites in human brains and that they are composed of β sheets of amyloid. The spherulites were identical in appearance to spherulites of Aβ42 formed in vitro which suggested that they may too be composed of Aβ. The physiological significance of this finding may be in its support of previous speculation that spherulites in human brain tissue are the 3-dimensional manifestations of what are otherwise identified as senile or neuritic plaques.

Keywords: Alzheimer's disease, amyloid-β, Congo red, human brain, senile plaque, spherulites, thioflavin T

DOI: 10.3233/JAD-2011-110071

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 43-46, 2011

Authors: Exley, Christopher | House, Emily | Polwart, Anthony | Esiri, Margaret M.

Article Type: Research Article

Abstract: The deposition in the brain of amyloid-β as beta sheet conformers associated with senile plaques and vasculature is frequently observed in Alzheimer's disease. While metals, primarily aluminum, iron, zinc, and copper, have been implicated in amyloidβ deposition in vivo, there are few data specifically relating brain metal burden with extent of amyloid pathologies in human brains. Herein brain tissue content of aluminum, iron, and copper are compared with burdens of amyloid-β, as senile plaques and as congophilic amyloid angiopathy, in 60 aged human brains. Significant observations were strong negative correlations between brain copper burden and the degree of severity of …both senile plaque and congophilic amyloid angiopathy pathologies with the relationship with the former reaching statistical significance. While we did not have access to the dementia status of the majority of the 60 brain donors, this knowledge for just 4 donors allowed us to speculate that diagnosis of dementia might be predicted by a combination of amyloid pathology and a ratio of the brain burden of copper to the brain burden of aluminum. Taking into account only those donor brains with either senile plaque scores ≥4 and/or congophilic amyloid angiopathy scores ≥12, a Cu : Al ratio of <20 would predict that at least 39 of the 60 donors would have been diagnosed as suffering from dementia. Future research should test the hypothesis that in individuals with moderate to severe amyloid pathology low brain copper is a predisposition to developing dementia. Show more

Keywords: Aluminum, Alzheimer's disease, amyloid-β, congophilic amyloid angiopathy, copper, iron, human brain tissue, senile plaque

DOI: 10.3233/JAD-2012-120766

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 725-730, 2012

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

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

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

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