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Alzheimer Disease: HELP
Articles from Stoke on Trent
Based on 26 articles published since 2010
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These are the 26 published articles about Alzheimer Disease that originated from Stoke on Trent during 2010-2020.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Aluminum Should Now Be Considered a Primary Etiological Factor in Alzheimer's Disease. 2017

Exley, Christopher. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK. ·J Alzheimers Dis Rep · Pubmed #30480226.

ABSTRACT: In this paper, I have summarized the experimental and largely clinical evidence that implicates aluminum as a primary etiological factor in Alzheimer's disease. The unequivocal neurotoxicity of aluminum must mean that when brain burdens of aluminum exceed toxic thresholds that it is inevitable that aluminum contributes toward disease. Aluminum acts as a catalyst for an earlier onset of Alzheimer's disease in individuals with or without concomitant predispositions, genetic or otherwise. Alzheimer's disease is not an inevitable consequence of aging in the absence of a brain burden of aluminum.

2 Editorial What is the risk of aluminium as a neurotoxin? 2014

Exley, Christopher. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK. ·Expert Rev Neurother · Pubmed #24779346.

ABSTRACT: Aluminium is neurotoxic. Its free ion, Al(3+) (aq), is highly biologically reactive and uniquely equipped to do damage to essential cellular (neuronal) biochemistry. This unequivocal fact must be the starting point in examining the risk posed by aluminium as a neurotoxin in humans. Aluminium is present in the human brain and it accumulates with age. The most recent research demonstrates that a significant proportion of individuals older than 70 years of age have a potentially pathological accumulation of aluminium somewhere in their brain. What are the symptoms of chronic aluminium intoxication in humans? What if neurodegenerative diseases such as Alzheimer's disease are the manifestation of the risk of aluminium as a neurotoxin? How might such an (outrageous) hypothesis be tested?

3 Review The Influence of Nicotinamide on Health and Disease in the Central Nervous System. 2018

Fricker, Rosemary A / Green, Emma L / Jenkins, Stuart I / Griffin, Síle M. ·School of Medicine and Institute for Science and Technology in Medicine, Keele University, Staffordshire, UK. ·Int J Tryptophan Res · Pubmed #29844677.

ABSTRACT: Nicotinamide, the amide form of vitamin B

4 Review Collapse in the elderly: rivastigmine-induced heart block and a literature review of the pharmacology of acetylcholinesterase inhibitors used in Alzheimer's disease. 2018

Alonge, Olushola / Iqbal, Fahad Mujtaba / Cifonelli, Elzbieta. ·Senior Health Department, St Georges University Hospital, London, UK. · Department of Medicine, Keele University, Newcastle under Lyme, UK. ·BMJ Case Rep · Pubmed #29666099.

ABSTRACT: Falls resulting in neck of femur fractures are common in the elderly. Often multiple comorbidities can make management and diagnosis of such a polyfactorial condition difficult, particularly with Alzheimer's dementia (AD). Indeed, poorly managed AD may contribute to falls. We present our management of an 87-year-old woman, on rivastigmine for AD, who presented with a collapse episode-attributed to rivastigmine-resulting in a neck of femur fracture. Furthermore, we perform a literature review of the pharmacology of acetylcholinesterase inhibitors and how their use in AD may contribute to bradyarrhythmias.

5 Review Why industry propaganda and political interference cannot disguise the inevitable role played by human exposure to aluminum in neurodegenerative diseases, including Alzheimer's disease. 2014

Exley, Christopher. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University , Stoke-on-Trent , UK. ·Front Neurol · Pubmed #25386158.

ABSTRACT: In the aluminum age, it is clearly unpalatable for aluminum, the globe's most successful metal, to be implicated in human disease. It is unpalatable because for approximately 100 years human beings have reaped the rewards of the most abundant metal of the Earth's crust without seriously considering the potential consequences for human health. The aluminum industry is a pillar of the developed and developing world and irrespective of the tyranny of human exposure to aluminum it cannot be challenged without significant consequences for businesses, economies, and governments. However, no matter how deep the dependency or unthinkable the withdrawal, science continues to document, if not too slowly, a burgeoning body burden of aluminum in human beings. Herein, I will make the case that it is inevitable both today and in the future that an individual's exposure to aluminum is impacting upon their health and is already contributing to, if not causing, chronic diseases such as Alzheimer's disease. This is the logical, if uncomfortable, consequence of living in the aluminum age.

6 Article Imaging of aluminium and amyloid β in neurodegenerative disease. 2020

Exley, Christopher / Mold, Matthew J. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, United Kingdom. ·Heliyon · Pubmed #32368656.

ABSTRACT: Objectives: Recent research has confirmed the presence of aluminium in human brain tissue. Quantitative analyses suggest increased brain aluminium content in a number of neurodegenerative diseases including familial Alzheimer's disease, congophilic amyloid angiopathy, epilepsy and autism. Complementary aluminium-specific fluorescence microscopy identifies the location of aluminium in human brain tissue and demonstrates significant differences in distribution between diseases. Herein we combine these approaches in investigating associations between aluminium in human brain tissue and specific disease-associated neuropathologies. Methods: We have used aluminium-specific fluorescence microscopy, Congo red staining using light and polarised light and thioflavin S fluorescence microscopy on serial sections of brain tissues to identify co-localisation of aluminium and amyloid β and tau neuropathology. Results: A combination of light, polarised and fluorescence microscopy demonstrates an intimate relationship between aluminium and amyloid β in familial Alzheimer's disease but not in other conditions and diseases, such as congophilic amyloid angiopathy and autism. We demonstrate preliminary evidence of amyloid β pathology, including associations with vasculature and parenchymal tissues, in autism in tissues heavily loaded with aluminium. Conclusion: We suggest that complementary aluminium-specific fluorescence microscopy may reveal important information about the putative toxicity of aluminium in neurodegenerative and neurodevelopmental disorders.

7 Article Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex. 2020

Viana, Gustavo Monteiro / Gonzalez, Esteban Alberto / Alvarez, Marcela Maciel Palacio / Cavalheiro, Renan Pelluzzi / do Nascimento, Cinthia Castro / Baldo, Guilherme / D'Almeida, Vânia / de Lima, Marcelo Andrade / Pshezhetsky, Alexey V / Nader, Helena Bonciani. ·Department of Biochemistry, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP 04044-020, Brazil. · Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS 90035-903, Brazil. · Department of Psychobiology, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP 04024-002, Brazil. · Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. · Division of Medical Genetics, CHU Ste-Justine Research Centre, Montreal, QC H3T 1C5, Canada. ·Int J Mol Sci · Pubmed #32093427.

ABSTRACT: Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-iduronidase and impairment of lysosomal catabolism of heparan sulfate and dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal proteases including cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of amyloid plaques due to an alternative pro-amyloidogenic processing of the amyloid precursor protein (APP), suggesting a potential role of this enzyme in the neuropathology of MPS I. In this study, we report elevated levels of protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (

8 Article Aluminum and Amyloid-β in Familial Alzheimer's Disease. 2020

Mold, Matthew / Linhart, Caroline / Gómez-Ramírez, Johana / Villegas-Lanau, Andrés / Exley, Christopher. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, United Kingdom. · Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Innsbruck, Austria. · Grupo de Neurociencias de Antioquia, Sede de Investigación Universitaria SIU, Medellín, Colombia. ·J Alzheimers Dis · Pubmed #31958088.

ABSTRACT: Genetic predispositions associated with metabolism of the amyloid-β protein precursor underlie familial Alzheimer's disease; a form of dementia characterized by early disease onset and elevated levels of cortical amyloid-β. Human exposure to aluminum is linked to the etiology of Alzheimer's disease and recent research measured a high content of aluminum in brain tissue in familial Alzheimer's disease. To elaborate upon this finding, we have obtained brain tissues from a Colombian cohort of donors with familial Alzheimer's disease. We have used established methods to measure the aluminum content of these tissues and we have compared the data with a recently measured dataset for control brain tissues. We report significantly higher levels of aluminum in brain tissues in donors with familial Alzheimer's disease than in control tissues from donors without neurological impairment or neurodegeneration. We have used aluminum-specific fluorescence microscopy along with complementary imaging for amyloid-β to demonstrate a very high degree of co-localization of these two risk factors in brain tissue in familial Alzheimer's disease. Aluminum and amyloid-β were co-located in senile plaques as well as vasculature, the latter resembling cerebral amyloid angiopathy. Aluminum was also found separately from amyloid-β in intracellular compartments including glia and neuronal axons. The research has identified an arguably unique association between high brain aluminum content and amyloid-β and allows postulation that genetic predispositions defining familial Alzheimer's disease underlie this relationship.

9 Article Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies. 2019

Lermyte, Frederik / Everett, James / Brooks, Jake / Bellingeri, Francesca / Billimoria, Kharmen / Sadler, Peter J / O'Connor, Peter B / Telling, Neil D / Collingwood, Joanna F. ·School of Engineering, University of Warwick, Coventry CV4 7AL, UK. f.lermyte@warwick.ac.uk. · Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. f.lermyte@warwick.ac.uk. · School of Engineering, University of Warwick, Coventry CV4 7AL, UK. j.everett@keele.ac.uk. · School of Pharmacy and Bioengineering, Keele University, Stoke-on-Trent, Staffordshire ST4 7QB, UK. j.everett@keele.ac.uk. · School of Engineering, University of Warwick, Coventry CV4 7AL, UK. j.brooks.1@warwick.ac.uk. · Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. f.bellingeri@warwick.ac.uk. · School of Engineering, University of Warwick, Coventry CV4 7AL, UK. k.billimoria@warwick.ac.uk. · MAS-CDT, University of Warwick, Coventry CV4 7AL, UK. k.billimoria@warwick.ac.uk. · Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. p.j.sadler@warwick.ac.uk. · Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. p.oconnor@warwick.ac.uk. · School of Pharmacy and Bioengineering, Keele University, Stoke-on-Trent, Staffordshire ST4 7QB, UK. n.d.telling@keele.ac.uk. · School of Engineering, University of Warwick, Coventry CV4 7AL, UK. J.F.Collingwood@warwick.ac.uk. · Materials Science and Engineering, University of Florida, Gainesville, FL 32611, USA. J.F.Collingwood@warwick.ac.uk. ·Cells · Pubmed #31658742.

ABSTRACT: Transition metals have essential roles in brain structure and function, and are associated with pathological processes in neurodegenerative disorders classed as proteinopathies. Synchrotron X-ray techniques, coupled with ultrahigh-resolution mass spectrometry, have been applied to study iron and copper interactions with amyloid β (1-42) or α-synuclein. Ex vivo tissue and in vitro systems were investigated, showing the capability to identify metal oxidation states, probe local chemical environments, and localize metal-peptide binding sites. Synchrotron experiments showed that the chemical reduction of ferric (Fe

10 Article Aluminium in human brain tissue: how much is too much? 2019

Exley, Christopher / Mold, Matthew J. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, ST5 5BG, UK. c.exley@keele.ac.uk. · The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, ST5 5BG, UK. ·J Biol Inorg Chem · Pubmed #31468176.

ABSTRACT: A burgeoning body of research confirms and affirms the presence of aluminium in human brain tissue. Recently, the first data on aluminium content of brain tissue from donors with diagnoses of familial Alzheimer's disease, autism spectrum disorder, multiple sclerosis and epilepsy have been published. Quantitative data are supported by aluminium-specific fluorescence microscopy identifying the locations of aluminium in human brain tissue. The challenge in the future will be to confirm or refute the role played by brain aluminium intoxication in human neurodegenerative disease.

11 Article Unequivocal imaging of aluminium in human cells and tissues by an improved method using morin. 2019

Mold, Matthew J / Kumar, Manpreet / Chu, William / Exley, Christopher. ·Aluminium and Silicon Research Group, The Birchall Centre, Lennard-Jones Laboratories, Keele University, Keele, Staffordshire, ST5 5BG, UK. m.j.mold@keele.ac.uk. · School of Life Sciences, Huxley Building, Keele University, Keele, Staffordshire, ST5 5BG, UK. · Aluminium and Silicon Research Group, The Birchall Centre, Lennard-Jones Laboratories, Keele University, Keele, Staffordshire, ST5 5BG, UK. ·Histochem Cell Biol · Pubmed #31463522.

ABSTRACT: Aluminium is biologically reactive and its ability to potentiate the immune response has driven its inclusion in both veterinary and human vaccines. Consequently, the need for unequivocal visualisation of aluminium in vivo has created a focused research effort to establish fluorescent molecular probes for this purpose. The most commonly used direct fluorescent labels for the detection of aluminium are morin (2',3,4',5,7-pentahydroxyflavone) and lumogallion [4-chloro-3-(2,4-dihydroxyphenylazo)-2-hydroxybenzene-1-sulphonic acid]. While the former has gained popularity in the detection of aluminium in plants and predominantly within root tips, the latter boasts greater sensitivity and selectivity for the detection of aluminium in human cells and tissues. Herein, we have developed a simplified morin staining protocol using the autofluorescence quenching agent, Sudan Black B. This modified protocol improves tissue morphology and increases analytical sensitivity, which allows intracellular aluminium to be detected in monocytes and when co-localised with senile plaques in human brain tissue of donors diagnosed with familial Alzheimer's disease. Overall, our results demonstrate a simple approach to minimise false positives in the use of morin to unequivocally detect aluminium in vivo.

12 Article A Glycosaminoglycan Extract from 2019

Mycroft-West, Courtney J / Cooper, Lynsay C / Devlin, Anthony J / Procter, Patricia / Guimond, Scott E / Guerrini, Marco / Fernig, David G / Lima, Marcelo A / Yates, Edwin A / Skidmore, Mark A. ·Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. c.j.mycroft-west@keele.ac.uk. · Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. l.c.cooper@keele.ac.uk. · Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. a.devlin1@keele.ac.uk. · Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133 Milan, Italy. a.devlin1@keele.ac.uk. · Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. p.procter@keele.ac.uk. · Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. s.e.guimond@keele.ac.uk. · Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire ST5 5BG, UK. s.e.guimond@keele.ac.uk. · Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133 Milan, Italy. guerrini@ronzoni.it. · School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK. dgfernig@liverpool.ac.uk. · Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. mlimagb@gmail.com. · Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. E.A.Yates@liverpool.ac.uk. · School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK. E.A.Yates@liverpool.ac.uk. · Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK. m.a.skidmore@keele.ac.uk. · Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire ST5 5BG, UK. m.a.skidmore@keele.ac.uk. · School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK. m.a.skidmore@keele.ac.uk. ·Mar Drugs · Pubmed #31100859.

ABSTRACT: Therapeutic options for Alzheimer's disease, the most common form of dementia, are currently restricted to palliative treatments. The glycosaminoglycan heparin, widely used as a clinical anticoagulant, has previously been shown to inhibit the Alzheimer's disease-relevant β-secretase 1 (BACE1). Despite this, the deployment of pharmaceutical heparin for the treatment of Alzheimer's disease is largely precluded by its potent anticoagulant activity. Furthermore, ongoing concerns regarding the use of mammalian-sourced heparins, primarily due to prion diseases and religious beliefs hinder the deployment of alternative heparin-based therapeutics. A marine-derived, heparan sulphate-containing glycosaminoglycan extract, isolated from the crab

13 Article Nanoscale synchrotron X-ray speciation of iron and calcium compounds in amyloid plaque cores from Alzheimer's disease subjects. 2018

Everett, James / Collingwood, Joanna F / Tjendana-Tjhin, Vindy / Brooks, Jake / Lermyte, Frederik / Plascencia-Villa, Germán / Hands-Portman, Ian / Dobson, Jon / Perry, George / Telling, Neil D. ·Institute for Science and Technology in Medicine, Thornburrow Drive, Keele University, Staffordshire, ST4 7QB, UK. ·Nanoscale · Pubmed #29688240.

ABSTRACT: Altered metabolism of biometals in the brain is a key feature of Alzheimer's disease, and biometal interactions with amyloid-β are linked to amyloid plaque formation. Iron-rich aggregates, including evidence for the mixed-valence iron oxide magnetite, are associated with amyloid plaques. To test the hypothesis that increased chemical reduction of iron, as observed in vitro in the presence of aggregating amyloid-β, may occur at sites of amyloid plaque formation in the human brain, the nanoscale distribution and physicochemical states of biometals, particularly iron, were characterised in isolated amyloid plaque cores from human Alzheimer's disease cases using synchrotron X-ray spectromicroscopy. In situ X-ray magnetic circular dichroism revealed the presence of magnetite: a finding supported by ptychographic observation of an iron oxide crystal with the morphology of biogenic magnetite. The exceptional sensitivity and specificity of X-ray spectromicroscopy, combining chemical and magnetic probes, allowed enhanced differentiation of the iron oxides phases present. This facilitated the discovery and speciation of ferrous-rich phases and lower oxidation state phases resembling zero-valent iron as well as magnetite. Sequestered calcium was discovered in two distinct mineral forms suggesting a dynamic process of amyloid plaque calcification in vivo. The range of iron oxidation states present and the direct observation of biogenic magnetite provide unparalleled support for the hypothesis that chemical reduction of iron arises in conjunction with the formation of amyloid plaques. These new findings raise challenging questions about the relative impacts of amyloid-β aggregation, plaque formation, and disrupted metal homeostasis on the oxidative burden observed in Alzheimer's disease.

14 Article Guidance for deriving and presenting percentage study weights in meta-analysis of test accuracy studies. 2018

Burke, Danielle L / Ensor, Joie / Snell, Kym I E / van der Windt, Danielle / Riley, Richard D. ·Research Institute for Primary Care and Health Sciences, Keele University, Keele, Staffordshire, ST5 5BG, UK. ·Res Synth Methods · Pubmed #29115060.

ABSTRACT: Percentage study weights in meta-analysis reveal the contribution of each study toward the overall summary results and are especially important when some studies are considered outliers or at high risk of bias. In meta-analyses of test accuracy reviews, such as a bivariate meta-analysis of sensitivity and specificity, the percentage study weights are not currently derived. Rather, the focus is on representing the precision of study estimates on receiver operating characteristic plots by scaling the points relative to the study sample size or to their standard error. In this article, we recommend that researchers should also provide the percentage study weights directly, and we propose a method to derive them based on a decomposition of Fisher information matrix. This method also generalises to a bivariate meta-regression so that percentage study weights can also be derived for estimates of study-level modifiers of test accuracy. Application is made to two meta-analyses examining test accuracy: one of ear temperature for diagnosis of fever in children and the other of positron emission tomography for diagnosis of Alzheimer's disease. These highlight that the percentage study weights provide important information that is otherwise hidden if the presentation only focuses on precision based on sample size or standard errors. Software code is provided for Stata, and we suggest that our proposed percentage weights should be routinely added on forest and receiver operating characteristic plots for sensitivity and specificity, to provide transparency of the contribution of each study toward the results. This has implications for the PRISMA-diagnostic test accuracy guidelines that are currently being produced.

15 Article Iron Biochemistry is Correlated with Amyloid Plaque Morphology in an Established Mouse Model of Alzheimer's Disease. 2017

Telling, Neil D / Everett, James / Collingwood, Joanna F / Dobson, Jon / van der Laan, Gerrit / Gallagher, Joseph J / Wang, Jian / Hitchcock, Adam P. ·Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, Staffordshire ST4 7QB, UK. Electronic address: n.d.telling@keele.ac.uk. · Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent, Staffordshire ST4 7QB, UK. · Warwick Engineering in Biomedicine, School of Engineering, University of Warwick, Coventry CV4 7AL, UK; Department of Materials Science and Engineering, University of Florida, Gainesville, FL 32611, USA. · Department of Materials Science and Engineering, University of Florida, Gainesville, FL 32611, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, Institute for Cell Engineering and Regenerative Medicine (ICERM), University of Florida, Gainesville, FL 32611, USA. · Magnetic Spectroscopy Group, Diamond Light Source, Didcot, Oxfordshire OX11 ODE, UK. · Department of Physiology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland. · Canadian Light Source Inc., 44 Innovation Boulevard, Saskatoon, SK S7N 2V3, Canada. · BIMR and Department of Chemistry, McMaster University, Hamilton, ON L8S 4M1, Canada. ·Cell Chem Biol · Pubmed #28890316.

ABSTRACT: A signature characteristic of Alzheimer's disease (AD) is aggregation of amyloid-beta (Aβ) fibrils in the brain. Nevertheless, the links between Aβ and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Aβ

16 Article Aluminium in brain tissue in familial Alzheimer's disease. 2017

Mirza, Ambreen / King, Andrew / Troakes, Claire / Exley, Christopher. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, ST5 5BG, United Kingdom. · Department Of Clinical Neuropathology, King's College Hospital, London, SE5 9RS, United Kingdom; MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, SE5 8AF, United Kingdom. · MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, SE5 8AF, United Kingdom. · The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, ST5 5BG, United Kingdom. Electronic address: c.exley@keele.ac.uk. ·J Trace Elem Med Biol · Pubmed #28159219.

ABSTRACT: The genetic predispositions which describe a diagnosis of familial Alzheimer's disease can be considered as cornerstones of the amyloid cascade hypothesis. Essentially they place the expression and metabolism of the amyloid precursor protein as the main tenet of disease aetiology. However, we do not know the cause of Alzheimer's disease and environmental factors may yet be shown to contribute towards its onset and progression. One such environmental factor is human exposure to aluminium and aluminium has been shown to be present in brain tissue in sporadic Alzheimer's disease. We have made the first ever measurements of aluminium in brain tissue from 12 donors diagnosed with familial Alzheimer's disease. The concentrations of aluminium were extremely high, for example, there were values in excess of 10μg/g tissue dry wt. in 5 of the 12 individuals. Overall, the concentrations were higher than all previous measurements of brain aluminium except cases of known aluminium-induced encephalopathy. We have supported our quantitative analyses using a novel method of aluminium-selective fluorescence microscopy to visualise aluminium in all lobes of every brain investigated. The unique quantitative data and the stunning images of aluminium in familial Alzheimer's disease brain tissue raise the spectre of aluminium's role in this devastating disease.

17 Article The Identification of Aluminum in Human Brain Tissue Using Lumogallion and Fluorescence Microscopy. 2016

Mirza, Ambreen / King, Andrew / Troakes, Claire / Exley, Christopher. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK. · Department of Clinical Neuropathology, King's College Hospital, London, UK. · MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK. ·J Alzheimers Dis · Pubmed #27472886.

ABSTRACT: Aluminum in human brain tissue is implicated in the etiologies of neurodegenerative diseases including Alzheimer's disease. While methods for the accurate and precise measurement of aluminum in human brain tissue are widely acknowledged, the same cannot be said for the visualization of aluminum. Herein we have used transversely-heated graphite furnace atomic absorption spectrometry to measure aluminum in the brain of a donor with Alzheimer's disease, and we have developed and validated fluorescence microscopy and the fluor lumogallion to show the presence of aluminum in the same tissue. Aluminum is observed as characteristic orange fluorescence that is neither reproduced by other metals nor explained by autofluorescence. This new and relatively simple method to visualize aluminum in human brain tissue should enable more rigorous testing of the aluminum hypothesis of Alzheimer's disease (and other neurological conditions) in the future.

18 Article Effects of transthyretin on thyroxine and β-amyloid removal from cerebrospinal fluid in mice. 2016

Chen, Ruoli / Chen, Carl P / Preston, Jane E. ·Institute of Pharmaceutical Science, King's College London, London, UK. · Institute of Science and Technology of Medicine, School of Pharmacy, Keele University, Staffordshire, UK. · Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan County, Taiwan, China. ·Clin Exp Pharmacol Physiol · Pubmed #27220110.

ABSTRACT: Transthyretin (TTR) is a binding protein for the thyroid hormone thyroxine (T4 ), retinol and β-amyloid peptide. TTR aids the transfer of T4 from the blood to the cerebrospinal fluid (CSF), but also prevents T4 loss from the blood-CSF barrier. It is, however, unclear whether TTR affects the clearance of β-amyloid from the CSF. This study aimed to investigate roles of TTR in β-amyloid and T4 efflux from the CSF. Eight-week-old 129sv male mice were anaesthetized and their lateral ventricles were cannulated. Mice were infused with artificial CSF containing (125) I-T4 /(3) H-mannitol, or (125) I-Aβ40/(3) H-inulin, in the presence or absence of TTR. Mice were decapitated at 2, 4, 8, 16, 24 minutes after injection. The whole brain was then removed and divided into different regions. The radioactivities in the brain were determined by liquid scintillation counting. At baseline, the net uptake of (125) I-T4 into the brain was significantly higher than that of (125) I-Aβ40, and the half time for efflux was shorter ((125) I-T4 , 5.16; (3) H-mannitol, 7.44; (125) I-Aβ40, 8.34; (3) H-inulin, 10.78 minutes). The presence of TTR increased the half time for efflux of (125) I-T4 efflux, and caused a noticeable increase in the uptake of (125) I-T4 and (125) I-Aβ40 in the choroid plexus, whilst uptakes of (3) H-mannitol and (3) H-inulin remained similar to control experiments. This study indicates that thyroxine and amyloid peptide effuse from the CSF using different transporters. TTR binds to thyroxine and amyloid peptide to prevent the loss of thyroxine from the brain and redistribute amyloid peptide to the choroid plexus.

19 Article The toxicity of aluminium in humans. 2016

Exley, C. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire ST5 5BG, United Kingdom. Electronic address: c.exley@keele.ac.uk. ·Morphologie · Pubmed #26922890.

ABSTRACT: We are living in the 'aluminium age'. Human exposure to aluminium is inevitable and, perhaps, inestimable. Aluminium's free metal cation, Alaq(3+), is highly biologically reactive and biologically available aluminium is non-essential and essentially toxic. Biologically reactive aluminium is present throughout the human body and while, rarely, it can be acutely toxic, much less is understood about chronic aluminium intoxication. Herein the question is asked as to how to diagnose aluminium toxicity in an individual. While there are as yet, no unequivocal answers to this problem, there are procedures to follow to ascertain the nature of human exposure to aluminium. It is also important to recognise critical factors in exposure regimes and specifically that not all forms of aluminium are toxicologically equivalent and not all routes of exposure are equivalent in their delivery of aluminium to target sites. To ascertain if Alzheimer's disease is a symptom of chronic aluminium intoxication over decades or breast cancer is aggravated by the topical application of an aluminium salt or if autism could result from an immune cascade initiated by an aluminium adjuvant requires that each of these is considered independently and in the light of the most up to date scientific evidence. The aluminium age has taught us that there are no inevitabilities where chronic aluminium toxicity is concerned though there are clear possibilities and these require proving or discounting but not simply ignored.

20 Article Hydration water mobility is enhanced around tau amyloid fibers. 2015

Fichou, Yann / Schirò, Giorgio / Gallat, François-Xavier / Laguri, Cedric / Moulin, Martine / Combet, Jérôme / Zamponi, Michaela / Härtlein, Michael / Picart, Catherine / Mossou, Estelle / Lortat-Jacob, Hugues / Colletier, Jacques-Philippe / Tobias, Douglas J / Weik, Martin. ·Université Grenoble Alpes, CNRS, and Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut de Biologie Structurale, 38044 Grenoble, France; martin.weik@ibs.fr yann.fichou@ibs.fr dtobias@uci.edu. · Université Grenoble Alpes, CNRS, and Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Institut de Biologie Structurale, 38044 Grenoble, France; · Life Sciences Group, Institut Laue-Langevin, 38000 Grenoble, France; · Institut Laue Langevin, 38000 Grenoble, France; Institut Charles Sadron CNRS-UdS, 67034 Strasbourg, France; · Jülich Centre for Neutron Science, outstation at Heinz Maier-Leibnitz Zentrum, Forschungszentrum Jülich GmbH, 85747 Garching, Germany; · CNRS, UMR 5628, LMGP, 38016 Grenoble, France; Université de Grenoble Alpes, Grenoble Institute of Technology, 38016 Grenoble, France; · Life Sciences Group, Institut Laue-Langevin, 38000 Grenoble, France; Faculty of Natural Sciences, Keele University, Staffordshire ST5 5BG, United Kingdom; and. · Department of Chemistry, University of California, Irvine, CA 92697-2025 martin.weik@ibs.fr yann.fichou@ibs.fr dtobias@uci.edu. ·Proc Natl Acad Sci U S A · Pubmed #25918405.

ABSTRACT: The paired helical filaments (PHF) formed by the intrinsically disordered human protein tau are one of the pathological hallmarks of Alzheimer disease. PHF are fibers of amyloid nature that are composed of a rigid core and an unstructured fuzzy coat. The mechanisms of fiber formation, in particular the role that hydration water might play, remain poorly understood. We combined protein deuteration, neutron scattering, and all-atom molecular dynamics simulations to study the dynamics of hydration water at the surface of fibers formed by the full-length human protein htau40. In comparison with monomeric tau, hydration water on the surface of tau fibers is more mobile, as evidenced by an increased fraction of translationally diffusing water molecules, a higher diffusion coefficient, and increased mean-squared displacements in neutron scattering experiments. Fibers formed by the hexapeptide (306)VQIVYK(311) were taken as a model for the tau fiber core and studied by molecular dynamics simulations, revealing that hydration water dynamics around the core domain is significantly reduced after fiber formation. Thus, an increase in water dynamics around the fuzzy coat is proposed to be at the origin of the experimentally observed increase in hydration water dynamics around the entire tau fiber. The observed increase in hydration water dynamics is suggested to promote fiber formation through entropic effects. Detection of the enhanced hydration water mobility around tau fibers is conjectured to potentially contribute to the early diagnosis of Alzheimer patients by diffusion MRI.

21 Article Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide β-amyloid (1-42). 2014

Everett, J / Céspedes, E / Shelford, L R / Exley, C / Collingwood, J F / Dobson, J / van der Laan, G / Jenkins, C A / Arenholz, E / Telling, N D. ·Institute for Science and Technology in Medicine, Keele University, , Stoke-on-Trent, Staffordshire ST4 7QB, UK. ·J R Soc Interface · Pubmed #24671940.

ABSTRACT: For decades, a link between increased levels of iron and areas of Alzheimer's disease (AD) pathology has been recognized, including AD lesions comprised of the peptide β-amyloid (Aβ). Despite many observations of this association, the relationship between Aβ and iron is poorly understood. Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aβ(1-42) and synthetic iron(III), reminiscent of ferric iron stores in the brain. We report Aβ to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aβ-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aβ, enabling the redox cycling of the iron. These results demonstrate the ability of Aβ to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD. These interactions between Aβ and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies.

22 Article Evidence of redox-active iron formation following aggregation of ferrihydrite and the Alzheimer's disease peptide β-amyloid. 2014

Everett, James / Céspedes, Eva / Shelford, Leigh R / Exley, Chris / Collingwood, Joanna F / Dobson, Jon / van der Laan, Gerrit / Jenkins, Catherine A / Arenholz, Elke / Telling, Neil D. ·Institute for Science and Technology in Medicine, Keele University , Stoke-on-Trent, Staffordshire ST4 7QB, United Kingdom. ·Inorg Chem · Pubmed #24559299.

ABSTRACT: Recent work has demonstrated increased levels of redox-active iron biominerals in Alzheimer's disease (AD) tissue. However, the origin, nature, and role of iron in AD pathology remains unclear. Using X-ray absorption, X-ray microspectroscopy, and electron microscopy techniques, we examined interactions between the AD peptide β-amyloid (Aβ) and ferrihydrite, which is the ferric form taken when iron is stored in humans. We report that Aβ is capable of reducing ferrihydrite to a pure iron(II) mineral where antiferromagnetically ordered Fe(2+) cations occupy two nonequivalent crystal symmetry sites. Examination of these iron(II) phases following air exposure revealed a material consistent with the iron(II)-rich mineral magnetite. These results demonstrate the capability of Aβ to induce the redox-active biominerals reported in AD tissue from natural iron precursors. Such interactions between Aβ and ferrihydrite shed light upon the processes of AD pathogenesis, while providing potential targets for future therapies.

23 Article Silicon-rich mineral water as a non-invasive test of the 'aluminum hypothesis' in Alzheimer's disease. 2013

Davenward, Samantha / Bentham, Peter / Wright, Jan / Crome, Peter / Job, Deborah / Polwart, Anthony / Exley, Christopher. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Stoke-on-Trent, Staffordshire, UK. ·J Alzheimers Dis · Pubmed #22976072.

ABSTRACT: There has been a plausible link between human exposure to aluminum and Alzheimer's disease for several decades. We contend that the only direct and ethically acceptable experimental test of the 'aluminum hypothesis', which would provide unequivocal data specific to the link, is to test the null hypothesis that a reduction in the body burden of aluminum to its lowest practical limit would have no influence upon the incidence, progression, or severity of Alzheimer's disease. Herein we are testing the hypothesis that silicon-rich mineral waters can be used as non-invasive methods to reduce the body burden of aluminum in individuals with Alzheimer's disease and a control group consisting of their carers and partners. We have shown that drinking up to 1 L of a silicon-rich mineral water each day for 12 weeks facilitated the removal of aluminum via the urine in both patient and control groups without any concomitant affect upon the urinary excretion of the essential metals, iron and copper. We have provided preliminary evidence that over 12 weeks of silicon-rich mineral water therapy the body burden of aluminum fell in individuals with Alzheimer's disease and, concomitantly, cognitive performance showed clinically relevant improvements in at least 3 out of 15 individuals. This is a first step in a much needed rigorous test of the 'aluminum hypothesis of Alzheimer's disease' and a longer term study involving many more individuals is now warranted.

24 Article Brain burdens of aluminum, iron, and copper and their relationships with amyloid-β pathology in 60 human brains. 2012

Exley, Christopher / House, Emily / Polwart, Anthony / Esiri, Margaret M. ·Lennard-Jones Laboratories, The Birchall Centre, Keele University, Staffordshire, UK. c.exley@chem.keele.ac.uk ·J Alzheimers Dis · Pubmed #22699848.

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 amyloid-β 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.

25 Article Aluminium, iron and copper in human brain tissues donated to the Medical Research Council's Cognitive Function and Ageing Study. 2012

House, Emily / Esiri, Margaret / Forster, Gill / Ince, Paul G / Exley, Christopher. ·The Birchall Centre, Lennard-Jones Laboratories, Keele University, Stoke-on-Trent, Staffordshire, ST5 5BG, UK. ·Metallomics · Pubmed #22045115.

ABSTRACT: Aluminium, iron and copper are all implicated in the aetiology of neurodegenerative diseases including Alzheimer's disease. However, there are very few large cohort studies of the content of these metals in aged human brains. We have used microwave digestion and TH GFAAS to measure aluminium, iron and copper in the temporal, frontal, occipital and parietal lobes of 60 brains donated to the Cognitive Function and Ageing Study. Every precaution was taken to reduce contamination of samples and acid digests to a minimum. Actual contamination was estimated by preparing a large number of (170+) method blanks which were interspersed within the full set of 700+ tissue digests. Subtraction of method blank values (MBV) from tissue digest values resulted in metal contents in all tissues in the range, MBV to 33 μg g(-1) dry wt. for aluminium, 112 to 8305 μg g(-1) dry wt. for iron and MBV to 384 μg g(-1) dry wt. for copper. While the median aluminium content for all tissues was 1.02 μg g(-1) dry wt. it was informative that 41 brains out of 60 included at least one tissue with an aluminium content which could be considered as potentially pathological (> 3.50 μg g(-1) dry wt.). The median content for iron was 286.16 μg g(-1) dry wt. and overall tissue iron contents were generally high which possibly reflected increased brain iron in ageing and in neurodegenerative disease. The median content for copper was 17.41 μg g(-1) dry wt. and overall tissue copper contents were lower than expected for aged brains but they were commensurate with aged brains showing signs of neurodegenerative disease. In this study we have shown, in particular, the value of carrying out significant numbers of method blanks to identify unknown sources of contamination. When these values are subtracted from tissue digest values the absolute metal contents could be considered as conservative and yet they may still reflect aspects of ageing and neurodegenerative disease in individual brains.

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