Biometals in Neurodegenerative Diseases: Mechanisms and Therapeutics

Biometals in Neurodegenerative Diseases: Mechanisms and Therapeutics is an authoritative and timely resource bringing together the major findings in the field for ease of access to those working in the field or with an interest in metals and their role in brain function, disease, and as therapeutic targets. Chapters cover metals in Alzheimer’s Disease, Parkinson’s Disease, Motor Neuron Disease, Autism and lysosomal storage disorders.

This book is written for academic researchers, clinicians and advanced graduate students studying or treating patients in neurodegeneration, neurochemistry, neurology and neurotoxicology. The scientific literature in this field is advancing rapidly, with approximately 300 publications per year adding to our knowledge of how biometals contribute to neurodegenerative diseases.

Despite this rapid increase in our understanding of biometals in brain disease, the fields of biomedicine and neuroscience have often overlooked this information. The need to bring the research on biometals in neurodegeneration to the forefront of biomedical research is essential in order to understand neurodegenerative disease processes and develop effective therapeutics.

• Authoritative and timely resource bringing together the major findings in the field for those with an interest in metals and their role in the brain function, disease, and as therapeutic targets
• Written for academic researchers, clinicians, and advanced graduate students studying, or treating, patients in neurodegeneration, neurochemistry, neurology and neurotoxicology
• Edited by international leaders in the field who have contributed greatly to the study of metals in neurodegenerative diseases

• Language: English
• Publisher: Academic Press
• Release date: Apr 28, 2017
• ISBN: 9780128045633

Book preview

Biometals in Neurodegenerative Diseases

Mechanisms and Therapeutics

Edited by

Anthony R. White

Cell and Molecular Biology

QIMR Berghofer Medical Research Institute,

Herston, QLD, Australia

Michael Aschner

Department of Molecular Pharmacology

Albert Einstein College of Medicine

Bronx, NY, United States

Lucio G. Costa

Department of Environmental and Occupational

Health Sciences University of Washington

Seattle, WA, United States

Ashley I. Bush

Florey Institute of Neuroscience and Mental Health

University of Melbourne

Parkville, VIC, Australia

Table of Contents

Cover

Title page

Copyright

Contributors

Preface

Chapter 1: Biometals and Alzheimer’s Disease

Abstract

Introduction

The Role of Copper in AD

The Role of Zinc in AD

The Role of Iron in AD

Therapeutic Targeting of Biometals in AD

Conclusions

Chapter 2: Copper in Alzheimer’s Disease

Abstract

Introduction

The Physiology of Copper

Copper Toxicity

Conclusions

Chapter 3: The Role of Selenium in Neurodegenerative Diseases

Abstract

Introduction

Selenoproteins and the Selenoproteome

Selenium and Alzheimer’s Disease

Parkinson’s Disease

Other Neurodegenerative Diseases

Conclusions

Chapter 4: Does HFE Genotype Impact Macrophage Phenotype in Disease Process and Therapeutic Response?

Abstract

Iron

Hemochromatosis

HFE

Macrophages

HFE Animal Models

Conclusions

Chapter 5: Chemical Elements and Oxidative Status in Neuroinflammation

Abstract

Introduction

Metal-Induced Neurotoxicity and Multiple Sclerosis

Metals and Oxidative Status in Multiple Sclerosis

Metals and Oxidative Status in Clinically Isolated Syndromes

Conclusions

Chapter 6: Metals and Neuroinflammation

Abstract

Introduction

Mechanisms by Which Metal Elements Can Incite Immune Activity

The Relation Between Reactive Oxygen and Nitrogen Species and Inflammation

Conclusions

Chapter 7: Metals and Prions: Twenty Years of Mining the Awe

Abstract

Prion Diseases

Prion Protein

Prion Protein Function

Copper and PrP

Zinc and PrP

Iron and PrP

Manganese and PrP

Metals in Prion Disease

Chelation Therapy and Prion Disease

Conclusions

Chapter 8: Manganese and Neurodegeneration

Abstract

Background

Mn Essentiality and Metabolic Functions

Mn Biokinetics and Homeostatic Control

Neurotoxicology of Mn

Biomonitoring of Mn in Patients Undergoing PN

Conclusions

Acknowledgment

Chapter 9: Zinc in Autism

Abstract

Introduction

Zinc Signaling in Autism

Therapeutic Strategies in Autism Based on Biometals

Conclusions

Chapter 10: Metals and Motor Neuron Disease

Abstract

List of Abbreviations

Introduction

Metal Exposure

Metals in ALS Cerebrospinal Fluid

Metals in ALS

Protection by Metallothionein

Metal Distribution in ALS

Genetic Aspects

Concluding Remarks

Chapter 11: Metals and Lysosomal Storage Disorders

Abstract

Introduction

Common Pathological Features of Lysosomal Storage Disorders

Description of Most Common Neurodegenerative LSDs Associated with Biometal Imbalance

Function and Regulation of Biometals

Role of Biometals and Biometal Binding Proteins in LSDs

Targeting Metals to Treat Disease

Chapter 12: Developmental Exposure to Metals and its Contribution to Age-Related Neurodegeneration

Abstract

Introduction

Developmental Exposure to Toxicants and Late Effects

Developmental Lead Exposure and Alzheimer's Disease

Developmental Arsenic Exposure and Alzheimer's Disease

Conclusions and Future Perspectives

Acknowledgment

Chapter 13: Metal Biology Associated with Huntington’s Disease

Abstract

Introduction

The Epidemiology of HD

The Symptoms of HD

The Neuropathology of HD

Biological Function of Wild-type and Pathogenic HTT Proteins

Autophagy and Metals in Huntington’s Disease

Exosomes and Metal in Huntington’s Disease

Environmental Factors Impacting HD

Metals in HD

Iron in HD

Copper in HD

Calcium in HD

Manganese in HD

Manganese Deposition: Brain Regions, Cell Types, and Cellular Organelles

Manganese Dyshomeostasis in HD

Mn-Dependent and Mn-Utilizing Enzymes

Intracellular pH and Metal Biology in HD

Metal-Related Clinical Interventions in HD

Conclusions and Future Directions

Chapter 14: Metal-Binding to Amyloid-β Peptide: Coordination, Aggregation, and Reactive Oxygen Species Production

Abstract

Introduction

Structure of the Metal-Aβ Complexes

Affinity of Metals to Aβ

Aggregation

Reactive Oxygen Species Induced Oxidative Stress

Conclusions

Acknowledgments

Chapter 15: Metals and Mitochondria in Neurodegeneration

Abstract

Introduction

Iron Dyshomeostasis

Copper Dislocation

Zinc Deficiency

Mitochondrial Dysfunction

Conclusions

Acknowledgments

Chapter 16: Metal Transporters in Neurodegeneration

Abstract

Iron Transporters and Neurodegeneration

Zinc Transporters and Neurodegeneration

Copper Transporters and Neurodegeneration

Manganese Transporters and Neurodegeneration

Magnesium Transporters and Neurodegeneration

Aluminum Transporters and Neurodegeneration

Conclusions

Chapter 17: Metal Imaging in the Brain

Abstract

Introduction

Introduction to MRI Physics

MRI Contrast Agents

Gadolinium

Iron

Copper

Manganese

Chapter 18: Metalloregulation of Protein Clearance: New Therapeutic Avenues for Neurodegenerative Diseases

Abstract

Introduction

Metalloregulation of the Ubiquitin Proteasome System: Implication in Neurodegenerative Diseases

Metals as Mediators of Autophagy-Lysosomal Response

Conclusions

Acknowledgments

Chapter 19: Metals and Autophagy in Neurotoxicity

Abstract

Introduction

Part 1 Metal-Related Neurotoxicity and Neurodegenerative Diseases

Part 2 Autophagy in Metal Neurotoxicity

Conclusions

Acknowledgments

Chapter 20: An Overview of Multifunctional Metal Chelators as Potential Treatments for Neurodegenerative Diseases

Abstract

Introduction

Parent Metal Chelators

Multifunctional Metal Chelators

Conclusions

Chapter 21: Abnormal Function of Metalloproteins Underlies Most Neurodegenerative Diseases

Abstract

Background

Biometals

Abnormal Biometal Levels and Distribution Underlie Most Forms of Neurodegeneration

Abnormal Metalloprotein Function Underlying Neurodegenerative Diseases

Neurodegenerative Diseases Caused by Mutation in Metalloproteins

Neurodegenerative Diseases Associated With Abnormal Metalloprotein Function

Neurodegenerative Diseases Involving Biometal Changes but Without a Clearly Identified Role for Metalloprotein Abnormities

Neurodegenerative Diseases Where No Major Role for Biometals or Metalloproteins Has Yet Been Identified

Conclusions

Index

Copyright

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Contributors

Alessandro Alimonti,     National Institute of Health, Rome, Italy

Michael Aschner,     Albert Einstein College of Medicine, Bronx, NY, United States

Terry Jo V. Bichell

Vanderbilt Brain Institute

Vanderbilt University Medical Center, Nashville, TN, United States

Stephen C. Bondy,     Center for Occupational and Environmental Health, University of California, Irvine, CA, United States

Valentina Borghesani

CNRS, LCC (Laboratory of Chemical Coordination)

University of Toulouse, Toulouse, France

Aaron B. Bowman

Vanderbilt Brain Institute

Vanderbilt University Medical Center, Nashville, TN, United States

Sonia Brescianini,     Center for Epidemiology, Surveillance and Health Promotion, National Institute of Health, Rome, Italy

David R. Brown,     University of Bath, Bath, United Kingdom

Maria C. Buscarinu,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Ashley I. Bush,     The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia

Bárbara R. Cardoso

The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia

University of São Paulo, São Paulo, Brazil

Benedetta Cerasoli,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Jingyuan Chen,     Fourth Military Medical University, Xi’an, China

James R. Connor,     The Pennsylvania State University College of Medicine, Hershey, PA, United States

Lucio G. Costa

University of Washington, Seattle, WA, United States

University of Parma, Parma, Italy

Peter J. Crouch,     University of Melbourne, Melbourne, VIC, Australia

Melisa del Barrio

CNRS, LCC (Laboratory of Chemical Coordination)

University of Toulouse, Toulouse, France

David C. Dorman,     North Carolina State University, Raleigh, NC, United States

Peter Faller,     Biometals and Biological Chemistry, Institute of Chemistry, UMR 7177, University of Strasbourg, Strasbourg, France

Michela Ferraldeschi,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Arianna Fornasiero,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Andreas M. Grabrucker

Institute for Anatomy and Cell Biology

WG molecular Analysis of Synaptopathies, Ulm University, Ulm, Germany

Stefanie Grabrucker,     Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany

Mark A. Greenough,     The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

Timothy C. Halbesma,     Vanderbilt University Medical Center, Nashville, TN, United States

Dominic J. Hare

The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC

University of Technology Sydney, Broadway, NSW, Australia

Christelle Hureau

CNRS, LCC (Laboratory of Chemical Coordination)

University of Toulouse, Toulouse, France

Hong Jiang

Medical College of Qingdao University

Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, China

Katja M. Kanninen,     A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

Henna Konttinen,     A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

Katarína Lejavová,     A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

Frank W. Lewis,     Northumbria University Newcastle, Newcastle, United Kingdom

Wenjing Luo,     Fourth Military Medical University, Xi’an, China

Tarja Malm,     A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

Dinamene Marques dos Santos,     University of Lisbon, Lisboa, Portugal

Ana P. Marreilha dos Santos,     University of Lisbon, Lisboa, Portugal

Carlo Mattei,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Rosella Mechelli,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Alexandra I. Mot,     University of Melbourne, Melbourne, VIC, Australia

Anne M. Nixon,     The Pennsylvania State University College of Medicine, Hershey, PA, United States

Carlos M. Opazo,     The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

George Perry,     The University of Texas at San Antonio (UTSA), San Antonio, TX, United States

Anna Pino,     National Institute of Health, Rome, Italy

Germán Plascencia-Villa,     The University of Texas at San Antonio (UTSA), San Antonio, TX, United States

Alejandra Ramírez Muñoz,     The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

Giovanni Ristori,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Silvia Romano,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Per M. Roos,     Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden

Carlo Salustri,     Institute of Cognitive Sciences and Technologies (CNR), Fatebenefratelli Hospital, Rome, Italy

Marco Salvetti,     Center for Experimental Neurological Therapies, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy

Mariacristina Siotto,     Don Carlo Gnocchi Foundation ONLUS, Italy

Rosanna Squitti,     IRCCS, Institute Center St. John of God Fatebenefratelli, Brescia, Italy

Maria A. Stazi,     National Institute of Health, Rome, Italy

Peng Su,     Fourth Military Medical University, Xi’an, China

David Tétard,     Northumbria University Newcastle, Newcastle, United Kingdom

K. Grace Tipps,     Vanderbilt University Medical Center, Nashville, TN, United States

Mariacarla Ventriglia,     Institute of Cognitive Sciences and Technologies (CNR), Fatebenefratelli Hospital, Rome, Italy

Anthony R. White,     QIMR Berghofer Medical Research Institute, Herston, QLD, Australia

Miguel José-Yacamán,     The University of Texas at San Antonio (UTSA), San Antonio, TX, United States

Preface

Biological metals (biometals) have key functions in the brain but can also induce degenerative changes due to abnormalities in homeostatic mechanisms. The scientific literature in this field is advancing rapidly with approximately 300 publications per year adding to our knowledge of how biometals contribute to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, motor neuron disease, and others. Despite this rapid increase in our understanding of biometals in brain disease, the fields of biomedicine and neuroscience have often overlooked this information. The need to bring the research on biometals in neurodegeneration to the forefront of biomedical research is essential if we are to understand neurodegenerative disease processes and develop effective therapeutics. There are currently few sources of consolidated research on biometals and neurodegeneration that are available to biomedical researchers, clinicians, students, and others. This book on biometals in neurodegeneration provides an authoritative and timely resource to bring together the major findings in the field for ease of access to those working in neuroscience or biomedicine, or with an interest in metals and their role in the brain function, disease, and as therapeutic targets.

Overview of chapters included in Biometals in Neurodegenerative Diseases: Mechanisms and Therapeutics.

Alzheimer’s disease is the leading form of neurodegeneration contributing to the majority of an estimated 36 million cases of dementia worldwide. With an ageing world population, estimates for global Alzheimer’s disease prevalence are in the order of 115 million patients by 2050. It is therefore fitting that the opening chapter of this book covers biometals in Alzheimer’s disease. Mot and Crouch (Chapter 1, pp. 1–18) provide a comprehensive insight into the contribution of biometals including copper, zinc, and iron in several major pathological features of Alzheimer’s disease including amyloid peptide aggregation and tau phosphorylation. The chapter finishes with an insight into where therapeutic approaches to biometal modulation in Alzheimer’s disease may progress in the future. Staying with the role of biometals in Alzheimer’s disease, Squitti et al. (Chapter 2, pp. 19–34) provides a deeper insight into the role of copper in this disorder, describing the pathways of copper metabolism and brain copper handling as well as interesting aspects of copper toxicity and the role of ceruloplasmin and nonceruloplasmin copper in Alzheimer’s disease. This is followed by a very interesting insight into a biometal that receives less coverage than it should, selenium and its role in neurodegeneration. This biometal forms a critical inorganic component of the amino acid selenocysteine, which is involved in at least 25 different proteins. Abnormal selenium stasis is found in many forms of leading neurodegenerative diseases, and selenium-based therapeutics have the potential to make significant impacts in these disorders as discussed by Cardoso et al. (Chapter 3, pp. 35–50).

The subsequent three chapters by Nixon and Connor (Chapter 4, pp. 51–66), Ferraldeschi et al. (Chapter 5, pp. 67–82) and Stephen Bondy (Chapter 6, pp. 83–94) cover important aspects of biometals in inflammation and how this modulates outcomes in neurodegeneration. Nixon and Connor et al. describe how the high iron (Fe) gene, HFE genotype, affects macrophage phenotype in disease. Mutations in HFE appear to alter macrophage (and microglial) iron distribution with potentially important outcomes for neurodegeneration. Ferraldeschi et al. follow this with an expanded insight into the role of biometals in oxidative-mediated neuroinflammatory processes, with a more detailed focus on biometal effects in multiple sclerosis. Bondy then provides a valuable account of the various mechanisms leading to biometal-mediated neuroinflammation, including the formation of haptens, the production of reactive oxygen and nitrogen species, the sequestering of reducing capacity and the formation of inflammation-provoking colloids.

David Brown (Chapter 7, pp. 95–116) brings us a very informative and insightful account of 20 years of metals research in prion diseases, dispelling some common myths and providing a comprehensive account of where we have come to in this field. Iron, zinc, copper, and manganese all have key roles to play in prion protein stasis in diseases, such as Creutzfeld–Jakob disease. Staying with the biometal, manganese, Marques dos Santos et al. (Chapter 8, pp. 117–152) provide an in-depth coverage of this element in neurodegeneration, providing valuable information on the role of manganese in neurobiology, environmental exposure in humans, and subsequent pathways to neurotoxicity and neurodegeneration.

Although autism spectrum disorder (ASD) is not classically categorized as a neurodegenerative disorder, there are shared comorbidities between ASD and neurodegenerative disorders including altered biometal stasis in the brain. Grabrucker and Grabrucker (Chapter 9, pp. 153–174) delve into the role of these biometal changes in ASDs, providing an interesting account of how biometals can affect neuro-synaptic functions resulting in the features that characterize ASD. Although a rare disorder, motor neuron disease (MND) has been the center of recent major international funding efforts. The disease is rapid with most cases fatal in 2–5 years after onset, and no long-term effective treatment exists. Although the cause in most cases remains unknown, Per Roos (Chapter 10, pp. 175–194) describes a key role for possible environmental exposure to biometals including lead, manganese, and mercury in disease etiology, and how these metals may contribute to neuropathological changes. In the last of the chapters covering the general role of biometals in neurodegeneration, Konttinen et al. (Chapter 11, pp. 195–216) cover important aspects of biometals in another group of rare disorders, the lysosomal storage diseases (LSDs). Lysosomes are key sites of biometal homeostasis, and abnormalities in lysosomal function as occurs in LSDs, leads to significant biometal abnormalities with potentially major impacts leading to neurodegeneration in these disorders.

The second half of this volume covers molecular and cellular aspects of metals in brain health, dysfunction, and neurotoxicity. Lucio G. Costa (Chapter 12, pp. 217–230) starts this section with a review of how environmental exposure to metals, such as lead and arsenic in early life can affect outcomes in later life neurodegeneration including Alzheimer’s disease. The mechanism of this predisposition is unclear but could be related to epigenetic changes induced by biometals. Bichell et al. (Chapter 13, pp. 231–264) follow this with an account of metal biology in Huntington’s disease including potential iron, copper, and manganese interactions with a range of homeostatic enzymes and proteins in the brain. Del Barrio et al. (Chapter 14, pp. 265–282) return us to Alzheimer’s disease again with a critical insight into the fundamental copper coordination by amyloid peptide, the major protein form deposited in Alzheimer’s brains. The review describes how copper drives aggregation and reactive oxygen species generation through interaction with the amyloid peptide.

Delving deeper into the cells of the brain, Plascencia-Villa et al. (Chapter 15, pp. 283–312) explore the role of biometals in mitochondrial function and how this contributes to a range of neurodegenerative disorders. Abnormalities in biometal handling in the cell powerhouse leads to major outcomes including reactive oxygen species formation, abnormal cell signaling, and altered energy production with important consequences for highly metabolic neurons. Another important aspect of biometal involvement in neurodegeneration is biometal transportation. Changes to key biometal transporters in the brain can have profound effects on the handling and action of copper, zinc, iron, manganese etc. And conversely, altered metal levels can affect transporter expression and localization. Hong Jiang (Chapter 16, pp. 313–348) provides a comprehensive coverage of metal transporters for the main neuro-metals and how changes to these transporters can underlie neurodegenerative outcomes.

One of the most important techniques used to understand how biometals contribute to neurodegeneration is metal imaging. David Dorman (Chapter 17, pp. 349–362) describes one of the central biometal imaging techniques applied to neurodegenerative disease, magnetic resonance imaging (MRI), and how it can be used to understand and differentiate the roles of iron, manganese, and copper in brain disorders. Brain protein accumulation is a major feature of most neurodegenerative diseases and is often associated with impaired mechanisms for clearance of aggregated or abnormally folded proteins. Ramírez Muñoz et al. (Chapter 18, pp. 363–376) describe how metals play a fundamental role in protein clearance and how this can be affected by abnormal metal homeostasis, contributing further to neurodegenerative disease pathology. Related to this, Su et al. (Chapter 19, pp. 377–398) contribute a key insight to the role of metals in autophagic processes. A key cellular mechanism for clearance of unwanted cell material, autophagy is a complex process involving many proteins and subcellular compartments. Studies have found major impairments to autophagy in neurodegenerative diseases and this is now a common putative therapeutic target. Su et al., explore the role of metals in autophagy and how abnormalities to metal homeostasis can contribute to pathological autophagic changes.

Of course, one of the major reasons for increasing our understanding of biometals in neurodegeneration is to develop therapeutic approaches for these disorders. In the penultimate chapter, Lewis and Tétard (Chapter 20, pp. 399–414) provide us with a comprehensive overview of metal chelators as potential new treatments for neurodegeneration. The future of these therapeutics appears to be in development of multifunctional agents that target metals and additional pathological features of neurodegeneration, such as oxidative stress. Time will tell if this approach provides much needed advances in neurodegenerative disease therapeutics. The final chapter by Kanninen and White (Chapter 21, pp. 415–438) then takes an overarching view of biometals in neurodegeneration and provides a review of the role for metalloproteins in many forms of neurodegenerative disease, leading us to consider whether neurodegenerative diseases should be categorized as metallopathies.

Whether student, clinician, or specialized biometals researcher, we hope that the reader will be able to gain exciting new insights into biometals and neurodegeneration. We believe that this volume will have an important place in the medical literature and provide a valuable reference source for many years in this major field of neurodegenerative disease research.

Anthony R. White

Michael Aschner

Lucio G. Costa

Ashley I. Bush

Chapter 1

Biometals and Alzheimer’s Disease

Alexandra I. Mot

Peter J. Crouch    University of Melbourne, Melbourne, VIC, Australia

Abstract

Maintaining metal ion homeostasis is essential for diverse cellular processes, particularly in the central nervous system. Changes to the transition metals, copper, zinc, and iron in Alzheimer’s disease (AD) have been extensively reported, especially in the brain, blood, and cerebrospinal fluid. Through interactions with disease-associated proteins, including amyloid precursor protein, the proteolytically cleaved peptide amyloid-beta (Aβ), and tau, these biometals play an important role in disease pathogenesis. Currently, no disease modifying therapy exists for AD and clinical trials over the past decade aimed at targeting established disease mechanisms have failed to alter disease progression. Targeting biometals in AD by restoring metal ion homeostasis represents an alternative potential therapeutic avenue.

Keywords

Alzheimer’s disease

biometals

copper

zinc

iron

amyloid precursor protein

amyloid-β

tau

metal-based therapies

Outline

Introduction

The Role of Copper in AD

The Role of Zinc in AD

The Role of Iron in AD

Therapeutic Targeting of Biometals in AD

Conclusions

References

Introduction

Alzheimer’s disease (AD) was first described in 1906 by Dr. Alois Alzheimer, and is now the third leading cause of death in industrial countries.¹ The disease is clinically characterized by the progressive loss of memory and other cognitive domains including language, attention, orientation, and problem solving abilities.² The biggest risk factor for AD is age,³ and given the ageing population demographic of our society the incidence of AD is likely to increase in the future. This highlights the urgent need for the development of effective disease-modifying therapies to halt or slow disease progression. Although the aetiology of sporadic AD remains largely unknown, the disease is associated with distinct pathological abnormalities which distinguish the condition from other forms of dementia.⁴ Macroscopically, AD is characterized by progressive cortical atrophy particularly of the frontal, parietal, and temporal lobes.⁵ Microscopically, the disease is characterized by neuronal and synaptic loss, extracellular senile plaques composed of aggregated amyloid beta (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated forms of the protein tau.⁶,⁷

According to the amyloid cascade hypothesis which was first suggested in 1992, the Aβ peptide plays a central role in AD pathogenesis.⁸ The amyloid precursor protein (APP) is cleaved through one of two pathways by the metalloproteinases α-secretase, γ-secretase, or the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE 1) which is a β-secretase.⁹ The nonamyloidogenic pathway involves cleavage of the extracellular APP domain by α-secretase followed by cleavage of the intramembranous domain by γ-secretase. By contrast, in the amyloidogenic pathway the initial cleavage of the extracellular APP domain is mediated by BACE 1 resulting in the production of the Aβ peptide.¹⁰ Although Aβ is generated in all brain regions and is ubiquitously expressed throughout the body, not all brain regions are affected.¹¹,¹² This indicates that Aβ expression alone is not sufficient to cause disease, and it is therefore likely that other factors in the affected brain regions are able to either induce Aβ toxicity or to make these brain regions in other ways vulnerable to disease. Consistent with this is the fact that phase three clinical trials performed on drugs that inhibit Aβ production or lower Aβ levels through immunotherapy have failed to alter disease progression.¹³–¹⁶ Alternative therapeutic approaches are therefore urgently needed.

Biologically functional metal ions (also known as biometals) are tightly regulated in the heathy brain and a breakdown in the homeostasis mechanisms that compartmentalize and regulate these metals can substantially affect brain function.¹⁷ The following sections will examine how copper, zinc, and iron play a role in AD pathogenesis through interactions with disease-associated proteins. Lastly, therapeutic attempts to restore biometal homeostasis in AD will be reviewed.

The Role of Copper in AD

Copper is a redox-active metal and exists in either oxidized (Cu²+) or reduced (Cu+) valence states.¹⁸ Many enzymes utilize this change in copper oxidation state, in the presence of oxygen, to catalyze redox chemistry for a wide range of important biochemical reactions. Some important copper-containing enzymes are: Cu/Zn-superoxide dismutase (SOD1), which converts the superoxide free radical into hydrogen peroxide,¹⁹ cytochrome c oxidase (COX) which plays a key role in the mitochondrial electron transport chain,²⁰ and ceruloplasmin (Cp) which functions as a ferroxidase to facilitate iron export from cells.²¹ All of these proteins require copper binding to perform their function, and low copper levels could therefore lead to oxidative stress, mitochondrial dysfunction, and intracellular iron accumulation, all of which are observed in AD.²²–²⁴ The same chemistry which makes copper useful in biology also allows free copper to catalyze the formation of the hydroxyl radical via the Fenton reaction.²⁵ Therefore, because the free form of the metal is potentially damaging, absorption and excretion of copper are tightly regulated in the body. Copper transport across cellular membranes occurs predominantly via the transporters high affinity copper uptake protein 1 (Ctr1) and ATPase copper-transporting alpha and beta polypeptides (ATP7a and ATP7b).²⁶ Neurodegeneration is a feature of both Menkes disease, which is caused by mutations in the gene encoding ATP7a²⁷,²⁸ and Wilson disease, which is caused by mutations in the gene encoding ATP7b.²⁹,³⁰ This demonstrates that copper dysregulation is detrimental to brain health.

In the AD brain overall copper levels are decreased within affected regions³¹,³² but are enriched within plaques and neurofibrillary tangles.³³ From this a complex picture emerges where abnormal copper distribution in AD leads to copper deficiency within affected brain regions. In the healthy brain, postsynaptic N-methyl-D-aspartic acid (NMDA) neurites release ionic copper into the synaptic cleft, facilitated by ATP7a, at a concentration of around 15 μM.³⁴,³⁵ Within the synaptic cleft copper causes S-nitrosylation of NMDA receptors, which inhibits their activation.³⁶ The sequestration of copper within amyloid plaques has been proposed as a mechanism by which the pool of free copper within the synaptic cleft is depleted leading to increased activation of NMDA receptors.³⁷ In contrast with decreased brain copper levels in AD, the serum and cerebrospinal fluid (CSF) levels of copper are significantly elevated in AD patients when compared to age-matched controls.³⁸,³⁹ This may correlate with increased expression of ceruloplasmin (a major copper-binding protein in serum) in AD, although excess copper is not bound to this carrier protein.⁴⁰ Furthermore, increased serum copper was reported to correlate well with higher levels of serum peroxides in AD patients.⁴¹ Taken together these studies indicate that altered copper distribution in AD brain, serum, and CSF contributes to disease pathogenesis.

Copper binds to APP in the amino-terminal ectodomain (between residues 142 and 166)⁴² and catalytically reduces copper (II) to copper (I).⁴³ The structure of the APP copper binding domain consist of four ligands (His-147, His-151, Tyr-168, and Met-170),⁴² which show structural homology to other copper chaperones. As a ubiquitously expressed protein, APP may play a role in regulating metal ion homeostasis. This is supported by studies which have shown that chronic copper overload or copper deficiency can both up- and downregulate APP mRNA expression in mouse fibroblasts.⁴⁴,⁴⁵ Furthermore, another study found that a low copper diet in healthy individuals was associated with decreased APP protein expression in platelets.⁴⁶ Conversely, both in vivo and in vitro studies in APP-knockout mice have shown that copper levels are significantly increased in brain and liver tissues as well as in cortical neuron and fibroblast primary cultures derived from these animals.⁴⁷,⁴⁸ One of these studies also found that APP-knockout primary cortical neurons are susceptible to copper-induced toxicity through copper (I) production which caused localized oxidative stress.⁴⁷ Moreover, the overexpression of mutant APP in various transgenic mouse lines decreased copper levels in both in vivo and in vitro contexts.⁴⁹–⁵¹ Additionally, copper promotes an increase in cell surface APP by increasing its exocytosis and reducing its endocytosis, respectively.⁵² Collectively these studies indicate that the interaction between copper and APP may contribute to AD pathogenesis.

Copper binds to the Aβ peptide in a pH-dependent manner and Aβ1–16 has been shown to be the minimal sequence required for copper binding.⁵³ Between pH 6 and 7, Aβ binds to copper at Asp1, His6, and His13/14; while at pH 8, the binding sites shift to His6, His13, and His14.⁵⁴ At pH 10 or higher, Asp1, Ala2, Glu3, and Phe4 can also form a complex with copper.⁵⁵,⁵⁶ Of particular interest is the fact that Aβ purified from human brain plaques contains fewer histidine residues, which has been explained by copper-mediated oxidation.⁵⁷ Copper modifies Aβ by promoting dityrosine crosslinking of the peptide, which may act as a seed to accelerate Aβ aggregation and induce oligomer formation.⁵⁸,⁵⁹ Aβ toxicity is partially dependant on copper and can be attenuated in cell culture by copper chelation.⁶⁰,⁶¹ The mechanism of copper-Aβ induced cytotoxicity might involve oxidative stress, as the complex catalytically generates hydrogen peroxide.⁶² Furthermore, another study found that the copper-Aβ complex could inhibit COX function thereby impairing mitochondrial energy production.⁶³

Copper also binds to the tau protein and certain fragments in the four-repeat microtubule-binding domain of tau (residues 256–273, 287–304, and 306–336) were shown to aggregate in the presence of copper in vitro.⁶⁴,⁶⁵ Furthermore, copper binding to tau induces hydrogen peroxide production,⁶⁶ which recapitulates what is observed in AD brains where copper-containing NFTs are a source of oxidative stress.⁶⁷ Chronic copper exposure accelerates tau hyperphosphorylation via abnormal cyclin-dependent kinase 5 (Cdk5) activation, resulting in dissociation of tau from microtubules in an AD mouse model.⁶⁸ However, copper delivery drugs have been shown to decrease glycogen synthase kinase 3 beta (GSK-3β)-dependent tau phosphorylation.⁶⁹ These studies indicate that copper alters tau phosphorylation through diverse mechanisms.

The Role of Zinc in AD

Zinc is another transition metal which plays an important role in diverse cellular functions. With the possible exception of pancreatic β islets, the brain contains the highest concentration of zinc within the body.⁷⁰ Within the healthy brain, the majority of zinc is compartmentalized in membrane-bound metalloproteins (particularly metallothioneins MT-I, II, and III).⁷¹ Diverse classes of proteins require bound zinc for normal function, including metalloenzymes (e.g., SOD1), transcription factors, and signaling kinases.⁷²,⁷³ In its free ionic form, zinc in the brain is highly enriched in glutamatergic nerve terminals where it is released (at concentrations of 1–100 μM) upon neuronal activation.⁷⁴ Synaptic zinc has a functional role in signal transmission and acts as an antagonist to NMDA receptors.⁷⁵ Intracellular zinc uptake is facilitated by a number of zinc-importing proteins (ZIPs), particularly ZIPs 1–5 and 7–15.⁷⁶ Zinc uptake can also be mediated by NMDA receptor-dependent voltage-gated L-type Ca²+, Ca²+-permeable AMPA/kainate channels, and Na+/Zn+ exchangers.⁷⁷–⁷⁹ Approximately 50% of zinc uptake requires the AD-linked presenilin protein, however, the mechanism by which presenilin contributes to zinc uptake is unknown.⁸⁰ Intracellular zinc sequestration or export occurs via the zinc transport (ZnT) protein family. ZnT-2, 5, 7, and 8 are expressed at low levels within the brain, while ZnT-3 is found in granule, pyramidal, and interneuron cells of the hippocampus and plays a role in transporting zinc into glutamatergic vesicles.⁸¹ Indeed, a loss of synaptic zinc in ZnT-3-knockout mice causes age-depend cognitive decline,⁸² demonstrating the importance of synaptic zinc in brain function.

Bulk tissue analyses of postmortem AD brains have yielded inconsistent results. Earlier work showed no difference in brain zinc levels between AD and controls,⁸³,⁸⁴ while latter studies showed a decrease in zinc levels in several AD brain regions including the neocortex, superior frontal and parietal gyri, medial temporal gyrus and thalamus, and the hippocampus.⁸⁵,⁸⁶ Conflicting reports have, however, also shown elevated zinc levels in multiple AD brain regions including the amygdala, hippocampus, cerebellum, olfactory areas, and superior temporal gyrus.³¹,⁸⁷ These discrepancies could be a result of the examination of different brain regions and/or the utilization of different sample preparations (e.g., tissue fixation affects zinc measurement).⁸⁸ Moreover, bulk tissue analyses are unlikely to reveal changes in zinc compartmentalization. Indeed, studies have shown that in AD there is a redistribution of zinc into extracellular plaques and surrounding neuropil.³³,⁸⁹ While the cause of zinc dysregulation in AD remains unknown, changes to several proteins involved in zinc homeostasis including MT-I, MT-II, MT-III, ZnT-1, ZnT-3, ZnT4, and ZnT-6 in AD⁹⁰–⁹³ are likely to contribute to the aberrant compartmentalization of zinc within the brain. Interestingly, estrogen can also modulate levels of ZnT-3 which is of particular significance given that sex is another major risk factor for AD.⁹⁴ The serum and CSF levels of zinc are decreased in AD patients when compared to age-matched controls,³⁸,⁹⁵ which could in part be explained by nutritional deficiency associated with advanced age.¹⁷

Zinc binds to APP in a conserved region of amino acids between residues 170 and 188 and this domain consists of two key cysteine ligands at position 186 and 187, which are crucial for binding as well as other potential ligands (e.g., Cys174, Met170, Asp177, and Glu184).⁹⁶,⁹⁷ Zinc interferes with APP processing by altering the function of key secretases involved in APP cleavage. A disintegrin and metalloproteinase domain-containing protein 10 (ADAM 10), the α-secretase involved in the nonamyloidogenic processing of APP, is a zinc-dependent enzyme and thus zinc increases APP proteolysis.⁹⁸ Zinc also increases presenilin 1 expression which facilities cellular zinc uptake,⁸⁰ although the activity of the γ-secretase complex is inhibited by zinc.⁹⁹ Furthermore, the binding of zinc to Aβ within the APP protein sequence can mask the proteolytic cleavage site,¹⁰⁰ thus inhibiting degradation of Aβ by matrix metalloproteases.¹⁰¹

Zinc binds to Aβ between residues 6 and 28 with up to three zinc ions bound to histidines 6, 13, and 14.⁹⁶,⁹⁷,¹⁰⁰ Zinc binding rapidly induces the aggregation of Aβ into insoluble precipitates, which typify AD pathology.¹⁰² Zinc-induced plaque formation in AD is also supported by the anatomical distribution of plaque and zinc in the brain. Although Aβ is ubiquitously expressed, plaque formation only occurs in neocortical regions of AD-affected brains which closely align with the expression of ZnT3.¹⁰³ APP transgenic mice crossed with ZnT3-knockout mice exhibited decreased Aβ burden,¹⁰³ which demonstrates the contribution of endogenous zinc to amyloid burden in AD. Furthermore, zinc sequestration into amyloid deposits induces loss of functional zinc in the synapse.¹⁰² Synaptic zinc deficiency is further exacerbated in AD by concomitant loss of ZnT3 expression.³³ Therefore, by two mechanisms labile zinc is made deficient in the brain neuropil in AD.

Zinc can directly bind to tau monomers with moderate affinity, altering its confirmation, and can induce both the fibrillization and the aggregation of the protein.¹⁰⁴,¹⁰⁵ Zinc also modulates the translation and phosphorylation of tau by affecting the activities of GSK-3β, protein kinase B, ERK1/2, and c-Jun N-terminal kinase.¹⁰⁶,¹⁰⁷ Furthermore, zinc is elevated in neurons with neurofibrillary tangle pathology.⁸⁹

The Role of Iron in AD

Iron is a transition metal which can exist in oxidation states from −2 to +8, but in biological systems only ferrous (Fe²+) and ferric (Fe³+) states exist. The cycling between Fe²+ and Fe³+ is utilized in biology for various electron transfer (redox) reactions essential to life.¹⁰⁸,¹⁰⁹ Furthermore, iron is required for other essential biological processes including: the transport of oxygen (where iron is bound to haemoglobin),¹¹⁰ regulation of protein expression,¹¹¹,¹¹² cell growth¹¹³ and cell differentiation,¹¹⁴ as well as brain development,¹¹⁵ neurotransmitter synthesis,¹¹⁶ and myelin production.¹¹⁷ Although essential to biological processes, when in excess, iron is toxic because it can react with oxygen through the Fenton reaction to generate superoxide anions and hydroxyl radicals,¹¹⁸ which are a source of oxidative stress.¹¹⁹ For these reasons iron levels are tightly regulated within the body and disruption of these homeostatic processes can cause either iron-deficient anemia or iron overload disorders.¹²⁰ Iron homeostasis is maintained via the coordinated action of several proteins including the iron carrier protein transferrin, the transferrin receptor for iron import, the ferroportin channel for iron export, the iron storage protein ferritin, ferrireductases which reduce iron to its ferrous state, and ferroxidases which oxidize iron to its ferric state. Circulation iron, once oxidized to its ferric state using the ferroxidase ceruloplasmin, cannot cross the blood brain barrier (BBB), but requires an iron complexed to transferrin to bind the transferrin receptor on the lumen side of endothelial cells.¹²¹,¹²² The transferrin complex then enters the cell via endocytosis where iron assimilates with a labile iron pool within the cytosol and is available for incorporation into iron-binding proteins, such as ferritin.¹²³ This process is highly regulated by the abundance or the deficiency in both transferrin (with or without iron incorporated) and its receptor.¹²⁴,¹²⁵

In the AD brain iron levels are elevated¹²⁶,¹²⁷ and especially enriched within neurofibrillary tangles²⁴ and amyloid plaques,¹²⁸ the latter of which has an iron concentration three times higher than that which is found in the surrounding normal neuropil.³³ Iron accumulation occurs in the AD cortex, but not the cerebellum, which is consistent with the anatomical profile of neurodegeneration in AD.¹²⁹,¹³⁰ The iron storage protein ferritin binds most iron within the brain,¹²⁷ and this protein increases with age and in AD.¹³¹ Neuronal iron deposition causes oxidative stress which likely contributes to elevated oxidative stress observed in the AD brain.¹³² Furthermore, iron-induced oxidative stress has been shown to initiate several apoptotic pathways in neurons and damage lipids and proteins (including the NMDA receptor) resulting in synaptic dysfunction and neuronal cell death.¹³³–¹³⁵ A number of iron-associated proteins have an altered expression profile in AD, which could partly explain the cause of iron accumulation in AD. Ferritin has been reported to be elevated in AD and colocalizes with amyloid plaques.¹²⁶ Transferrin, which is normally expressed solely by oligodendrocytes, is also expressed in astrocytes in the AD brain¹²⁶ and was found to be increased in frontal cortex of AD.¹³⁶ Lower ceruloplasmin expression was found in AD brains,¹³⁷ as well as its ferroxidase activity in plasma.¹³⁸ Taken together, it is likely that the iron accumulation observed in AD is a result of multiple failures in its regulatory proteins. Reports of iron levels in serum and CSF have yet to show a consistent change in AD.³⁸,¹³⁹ While serum iron levels may be unchanged, a recent study has shown that CSF ferritin levels can predict AD outcomes.¹⁴⁰

Iron binds to APP via the iron-responsive element type II located within the 5’ untranslated region of its mRNA sequence.¹⁴¹ Under conditions of high iron levels, such as are seen in the AD brain, restricted translation of APP by iron-responsive proteins is diminished, leading to increased translation of the transcript.¹¹¹ Conversely, the same study also found that iron chelation decreased translation of the transcript. Iron may also alter APP cleavage by modulating furin, a proconvertase involved in the regulation of α-secretase-dependent processing.¹⁴² Since ferrous iron has a low affinity for transferrin, it requires oxidation by a ferroxidase before it can be removed from the cell.¹⁴³ Ceruloplasmin is the classic ferroxidase¹⁴⁴,¹⁴⁵; however, this protein is not expressed in neurons.¹⁴⁶ In one recent study APP was proposed as the analogous neuronal ferroxidase.¹²⁹ This study found that APP-knockout mice exhibit iron accumulation in brain and peripheral tissues, and loss of APP ferroxidases activity in the AD brain is coincident with iron retention in the tissue.

Iron in both Fe²+ and Fe³+ states binds to the Aβ peptide at residues Asp1, Glu3, His6, His13, and His14.¹⁴⁷,¹⁴⁸ Iron promotes the aggregation of Aβ in vitro,¹⁴⁹ which can be prevented by iron chelation.¹⁵⁰ The iron-aggregated Aβ is also toxic to cultured cells,¹⁵¹,¹⁵² which has been suggested to be mediated by reactive oxygen species,¹⁵³ by Fenton chemistry,¹⁵⁴ or by the activation of the Bcl-2-related apoptosis pathway.¹⁵⁵ Taken together, these studies suggest a role for iron-mediated Aβ toxicity in AD.

Iron also binds to the tau protein, and the binding of Fe³+, but not Fe²+, causes aggregation of hyperphosphorylated tau that can be reversed by reducing Fe³+ to Fe²+ or by iron chelation.¹⁵⁶,¹⁵⁷ Within the AD brain, iron enrichment colocalizes with NFTs and is a source of reactive oxygen species.²⁴,⁶⁷ Iron also affects the phosphorylation status of tau: Fe³+ decreases tau phosphorylation¹⁵⁸ while Fe²+ increases tau phosphorylation.¹⁵⁹,¹⁶⁰ Furthermore, a recent study has shown that the iron-export capability of APP requires the binding of tau to APP.¹⁶¹,¹⁶² In tau-knockout primary cortical neurons, APP was inappropriately trafficked and not presented on the extracellular surface where it acts as a ferroxidase.¹⁶¹ Total tau levels are decreased in the AD cortex,¹⁶³,¹⁶⁴ and loss of tau expression causes iron- and age-dependent cognitive loss and cortical atrophy in mice.¹⁶¹ These studies demonstrate the apparent interconnection between iron overload, tau, and APP in the pathogenesis of AD.

Therapeutic Targeting of Biometals in AD

Given that targeting Aβ in multiple ways has so far failed to confer clinical benefits,¹³–¹⁶ there is a need to target other pathways in AD. Targeting biometals by restoring metal ion homeostasis represents an alternative potential therapeutic avenue. To achieve this, sophisticated compounds are needed which can correct metal miscompartmentalization in AD by redistributing metal ions from extracellular plaques (preventing Aβ aggregation) into metal ion-deficient neurons (to restore normal function). Several potential metal-based AD therapeutics are discussed later.

5-Chloro-7-iodo-quinolin-8-ol (clioquinol) is a derivative of 8-hydroxyquinoline that was widely used as an antiparasitic agent before it was withdrawn from clinical use owing to a speculated severe side effect, subacute myelo-optic-neuropathy (SMON). This side effect was only observed in Japan,¹⁶⁵ and the association between SMON and clioquinol has since been questioned.¹⁶⁶ Although it was initially considered a moderate chelator of iron, copper, and zinc,¹⁶⁷ clioquinol has more recently been characterized as a copper/zinc ionophore, which functions to redistribute these metals into cells.¹⁶⁸,¹⁶⁹ In addition, clioquinol is believed to confer neuroprotection by iron chelation, as iron binds to clioquinol,¹⁷⁰ and a number of the reported beneficial effects of clioquinol are iron dependent.¹⁵⁴,¹⁷¹ Preclinical studies have shown promising outcomes, including deceased Aβ brain burden,¹⁶⁶ inhibition of Aβ oligomer formation,¹⁷²,¹⁷³ and rescue of memory impairment in clioquinol treated animals.¹⁶⁶ Furthermore, a phase two clinical trial¹⁷⁴ and a case study¹⁷⁵ reported improvement in cognitive outcomes for patients with AD. However, complications with large-scale manufacturing of the compound have hindered further exploration for its use in AD.

A second-generation 8-hydroxyquinoline derivative, PBT2, has shown even greater therapeutic efficiency in an AD mouse model¹⁷⁶ as well as in a phase two clinical trial.¹⁷⁷,¹⁷⁸ However, in another more recent phase two clinical trial, PBT2 did not show an improved Pittsburgh compound B-PET scan when compared to placebo patients.¹⁷⁹ While patients on PBT2 had a lower Pittsburgh compound B-PET signal, the result was confounded by an inexplicable reduction in the placebo group. The proposed mechanism for neuroprotection of this drug is by acting as a copper-zinc ionophore, redistributing copper and zinc inside the cell, which induces inhibitory phosphorylation of the α- and β-isoforms of GSK-3 and subsequently lowers Aβ levels.¹⁸⁰ More comprehensive clinical studies are needed to further investigate the utility of this compound as an AD therapeutic.

Given that the mechanisms of action for both clioquinol and PBT2 probably involve their copper ionophore activity, copper-containing bis(thiosemicarbazone) compounds have been explored for their potential to treat AD. One compound, CuII(gtsm), delivers copper to neurons and has been shown to lower Aβ levels, GSK3β activity, and tau phosphorylation levels in cell culture and AD model mice, which was accompanied by improved cognition in these mice.⁶⁹,¹⁸¹ Another compound, CuII(atsm), delivers copper selectively to cells with an impaired electron transport chain¹⁸² and has not been shown to be beneficial in the APP/PS1 mouse model of AD.⁶⁹ Further studies are needed to examine the utility of these copper-containing bis(thiosemicarbazone) ligands for the treatment of AD.

Given the role for iron in regulating APP translation,¹¹¹ decreasing iron overload in AD via iron chelators has shown promise in both preclinical and clinical trials. The iron chelators epigallocatechin-3-gallate (EGCG) and M-30 have been shown to reduce APP expression in cultured cells.¹⁸³,¹⁸⁴ Furthermore, the iron chelator deferoxamine inhibits amyloidogenic APP processing in cultured cells and in AD model mice, which also attenuated Aβ burden within the brain and reversed spatial memory impairment.¹⁸⁵,¹⁸⁶ Intramuscular injection of deferoxamine was tested in a single-blind clinical trial of 48 AD patients over a 24-month period and deferoxamine treatment reduced the rate of cognitive decline by half.¹⁸⁷ Despite this encouraging trial outcome obtained in 1991, further clinical developments of compounds that target iron in AD have not occurred.

Conclusions

Through interactions with disease-associated proteins, including APP, Aβ, and tau, the biometals copper, zinc, and iron appear to play an important role in AD pathogenesis (Table 1.1). Altered biometal homeostasis in AD has opened up new opportunities for the development of disease-modifying therapeutics. Preclinical and clinical data indicate that targeting biometals by restoring metal ion homeostasis remains a promising prospect for the treatment of AD.

Table 1.1

Biometal Interactions With Disease-Associated Proteins in Alzheimer’s Disease

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