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Metal species and Alzheimer's disease

(20.11.2006)


Background:
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. It is the most common type of dementia. Alzheimer's disease has been identified as a protein misfolding disease due to the accumulation of abnormally folded amyloid beta protein in the brains of AD patients. Its causes are still largely unknown but various metals have been implicated as possible contributors to the development of AD.

Figure: Prevalence of Alzheimer disease in different age groups

In a special double issue of the Journal of Alzheimer’s Disease published in November 2006, guest editors Andrei C. Miu and Oana Benga have brought together 14 articles exploring the roles that metal species play in the biochemistry and physiology of AD. These articles cover six major categories: Comprehensive historical reviews, methodological perspectives, a topical review, integrative genetic and epigenetic reports, a review of risk factors and a “benchmark to clinical” review.

From guest editors Andrei C. Miu and Oana Benga: “We are grateful to the authors who accepted our challenge and who have shown that metallobiologists working in AD research have been less fascinated with describing end-stage pathognomonic lesions, and more concerned with identifying risk and aggravating factors that might help us better predict, diagnose and hopefully prevent AD in the future.”

The content of the special issue:
John Savory, Mary M. Herman and Othman Ghribi review the four-decades-old controversy about aluminum neurotoxicity, examining data on the possible cellular mechanisms underlying aluminum neurotoxicity and potential neuroprotective strategies against aluminum toxicity. In the next review, Paul A. Adlard and Ashley I. Bush discuss how metal ions such as zinc and copper can potentiate Alzheimer’s disease by participating in the aggregation of normal cellular proteins and in the generation of reactive oxygen species. In the third review article, Arezoo Campbell focuses on how aluminum and copper can initiate or propagate an inflammatory response in the aging brain. Christopher Exley reviews in-vitro studies of metals found in plaque cores in AD brains and concludes that aluminum and iron could cause oxidative damage but copper and zinc likely do not. In the final review article, Andrei C. Miu and Oana Benga recount the long history of aluminum’s hypothetical role in AD. They extensively discuss several lines of evidence for involvement of aluminum as a secondary aggravating factor or risk factor and argue that further studies are warranted.

Bettina Platt discusses the methodologies that have been used to identify Alzheimer- and dementia-related targets for exogenous toxins. She explains how neuronal function can be assessed experimentally, based on the evidence obtained for the neurotoxin aluminum. In the second article on methods, Joanna Collingwood and Jon Dobson write about recent approaches to locate and identify iron compounds in neurodegenerative tissue. In addition to complementary techniques that allow them to quantify and identify iron compounds using magnetometry, extraction and electron microscopy, they utilize a powerful combined mapping/characterization approach with synchrotron X-rays.

The movement of metals across the blood-brain barrier is reviewed by Robert A. Yokel. A number of transporters are described that could mediate metal transport into and out of the brain. He reviews the role of these transporters in moving aluminum, manganese, iron and other metals across the blood-brain barrier.

Hani Atamna has developed a novel model of amyloid-beta induced heme-deficiency that could account for neurodegeneration in AD patients. He reviews the genetic, nutritional and toxicological factors that influence heme metabolism and their relevance to AD. James R. Connor and Sang Y. Lee discuss genetic mutations in the HFE gene that can affect iron balance in the brain, potentially leading to the generation of reactive oxygen and oxidative damage. In a study of the presenilins (PS), Nazneen N. Dewji discusses how these proteins can trigger a cascade of processes that lead to amyloid-beta production, leading to AD. He reviews the structures of the PS proteins that can support the model of a surface reaction between two nearby brain cells. Iftach Dolev and Daniel M. Michaelson write about the apoE4 isoform of apolipoprotein E. Their study of the nucleation, growth and reversibility of amyloid-beta deposition in mice should shed new light on this genetic risk factor for AD.

Vincenzo Solfrizzi and co-authors review the possible role of macronutrients and the basic elements of carbohydrates, proteins, and fat in the development of AD. They suggest that healthy diets, antioxidant supplements, and the prevention of nutritional deficiencies or exposure to foods and water with high content of metals could be considered the first line of defense against the development and progression of cognitive decline.

In the final article, Jose L. Domingo focuses on the role of aluminum and metals such as copper and zinc in AD, as well as on metal chelator therapy as a potential treatment for AD. The effects of aluminum, copper and zinc chelating agents on amyloid-beta plaques are reviewed.


The Special Issue: Metals in Alzheimer's Disease edited by Andrei Miu and Oana Benga; Program of Cognitive Neuroscience, Department of Psychology, Babes¸-Bolyai University, Cluj-Napoca, CJ, Romania, J. Alzheimer Dis., 10/2-3 (2006)

Andrei C. Miu and Oana Benga, Foreword: Metals in Alzheimer's Disease, J. Alzheimer Dis., 10/2-3 (2006) 133.

John Savory, Mary M. Herman, Othman Ghribi, Mechanisms of aluminum-induced neurodegeneration in animals: implications for Alzheimer's disease, J. Alzheimer Dis., 10/2-3 (2006) 135-144.

Paul A. Adlard, Ashley I. Bush, Metals and Alzheimer’s disease, J. Alzheimer Dis., 10/2-3 (2006) 145-163.

Arezoo Campbell, The role of aluminum and copper on neuroinflammation and Alzheimer’s disease, J. Alzheimer Dis., 10/2-3 (2006) 165-172.

Christopher Exley, Aluminium and iron, but neither copper nor zinc, are key to the precipitation of ß-sheets of Aß42 in senile plaque cores in Alzheimer’s disease, J. Alzheimer Dis., 10/2-3 (2006) 173-177.

Andrei C. Miu and Oana Benga, Aluminum and Alzheimer's disease: a new look, J. Alzheimer Dis., 10/2-3 (2006) 179-201.

Bettina Platt, Experimental approaches to assess metallotoxicity and ageing in models of Alzheimer’s disease, J. Alzheimer Dis., 10/2-3 (2006) 203-213.

Joanna Collingwood and Jon Dobson, Mapping and characterization of iron compounds in Alzheimer’s tissue, J. Alzheimer Dis., 10/2-3 (2006) 215-222.

Robert A. Yokel, Blood-Brain Barrier Flux of Aluminum, Manganese, Iron and Other Metals Suspected to Contribute to Metal-Induced Neurodegeneration, J. Alzheimer Dis., 10/2-3 (2006) 223-253.

Hani Atamna, Heme Binding to Amyloid-ß Peptide: A Mechanism for Neuroprotection from Alzheimer’s Disease, J. Alzheimer Dis., 10/2-3 (2006) 255-266.

James R. Connor and Sang Y. Lee, HFE Mutations and Alzheimer’s Disease, J. Alzheimer Dis., 10/2-3 (2006) 267-276.

Nazneen N. Dewji, Presenilin structure in mechanisms leading to Alzheimer’s disease, J. Alzheimer Dis., 10/2-3 (2006) 277-290.

Iftach Dolev, Daniel M. Michaelson, The Nucleation Growth and Reversibility of Amyloid-ß Deposition in vivo, J. Alzheimer Dis., 10/2-3 (2006) 291-301.

Vincenzo Solfrizzi, Anna Maria Colacicco, Alessia D’Introno, Cristiano Capurso, Angelo Del Parigi, Sabrina A. Capurso, Francesco Torres, Antonio Capurso, Francesco Panza, Macronutrients, aluminium from drinking water and foods, and other metals in cognitive decline and dementia, J. Alzheimer Dis., 10/2-3 (2006) 303-330.

 Jose L. Domingo, Aluminum and other metals in Alzheimer’s disease: A review of potential therapy with chelating agents, J. Alzheimer Dis., 10/2-3 (2006) 331-341.


Related Studies

E. Gauthier, I. Fortier, F. Courchesne, P. Pepin, J. Mortimer, D. Gaovreau, Aluminium forms in drinking waters and risk for Alzheimer's Disease, Environ. Res. (U.S.A), 84/3 (2000) 234-246. doi:10.1006/enrs.2000.4101

Andreas Prange, Dirk Schaumlöffel, Peter Brätter, Andrea-Nicole Richarz, Christian Wolf, Species analysis of metallothionein isoforms in human brain cytochrome by use of capillary electrophoresis hyphenated to inductively coupled plasma-sector field mass spectrometry, Fresenius J. Anal. Chem., 371/6 (2001) 764-774.

J.S. Becker, M. Zoriy, C. Pickhardt, M. Przybylski, Johanna Sabine Becker, Investigation of Cu-, Zn- and Fe-containing human brain proteins using isotopic-enriched tracers by LA-ICP-MS and MALDI-FT-ICR-MS, Int. J. Mass Spectrom., 242/2-3 (2005) 135-144. doi: 10.1016/j.ijms.2004.10.027

Ari Ide-Ektessabi, Mariona Rabionet, The Role of Trace Metallic Elements in Neurodegenerative Disorders: Quantitative Analysis Using XRF and XANES Spectroscopy, Anal. Sci., 21/7 (2005) 885. DOI: 10.2116/analsci.21.885

Ayesha Khan, Jon P. Dobson, Christopher Exley, Redox cycling of iron by Aß42, Free Radic. Biol. Med., 40/4 (2006) 557-569. doi: 10.1016/j.freeradbiomed.2005.09.013

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