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Abstract and Introduction
Abstract
There is an evolving field of metallobiology that has begun to describe a key role for bioavailable metals (particularly copper, zinc and iron) in the pathogenesis of Alzheimer's disease (AD). In particular, there is an apparent failure in metal ion homeostasis, potentially caused by a pathological mislocalization of the metals in the brain, which appears to be an obligatory step in both the precipitation and potentiation of the disease. A number of both preclinical and clinical studies have also provided a strong burden of proof that normalizing metal ion homeostasis represents a valid therapeutic target, and may indeed represent the first disease-modifying strategy for AD. The role of metals in the pathophysiology of AD will be discussed in this article.
Introduction
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that was first identified in a case report by Alois Alzheimer in 1906, and which was formally defined as 'AD' by Emil Kraepelin in his text book of psychiatry in 1910. AD is the leading cause of dementia, affecting approximately 2% of the population of industrialized countries (˜12 million people), with a yearly societal cost in the hundreds of billions of dollars. The epidemiology, genetics and pathophysiology of the disease have been extensively studied and reported and will not be reviewed in this article. Instead, we will explore the interactions between amyloid-β (Aβ), one of the key proteins involved in the pathogenesis of AD and possibly a causative agent of the disease, and metals. We will approach this both from a basic biochemistry perspective and from a therapeutic standpoint, with a focus on the preclinical and clinical evidence supporting metal modulation (copper, zinc and iron) as an intervention strategy in AD.
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