Neurodegenerative Diseases Associated with Metals

FIGURE 21.6 Oxidative stress in parkinson s disease. (From Taicco et al, 2004. Copyright 2004 with permission from Nature.) 

There is considerable evidence that defective homeostasis of redox-active metals, i.e., iron and copper, together with oxidative stress, contributes to the neuropathology of AD. The characteristic histology of AD is the deposition of both A3, as neurotic plaques, and of the protein tau, as neurofibrillary tangles NFT, predominantly in the cerebral cortex and hippocampus. 

It has been suggested that the formation of the (3-sheet configuration of A(3 may actually be a protective mechanism, and that the increased synthesis of APP and A (3 is an attempt by the brain cells to detoxify the elevated 

FIGURE 21.9 Models of zinc and copper in the glutamatergic synapse in health and in Alzheimer s disease (a) the healthy synapse (b) Alzheimer s disease synapse. (From Duce Bush 2010. Copyright 2010 with permission from Elsevier.) 

FIGURE 21.10 Frataxin mutations. The commonest mutation is the GAA expansion in the first intron of the frataxin gene (98%). Boxes represent exons and blue bars introns of the frataxin gene. Asterisks indicate the number of families reported with each mutation. (From Durr, 2002. Copyright 2002 with permission from Elsevier.) 

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Metal-based Neurodegeneration Neurodegenerative Diseases Associated with Metals... 

Over the last decade, it has become more and more widely accepted that inflammation, associated with dysfunction of metal ion homeostasis (Fe, Cu, and Zn) accompanied by concomitant oxidative stress, is a key factor in a large number of neurodegenerative diseases such as Alzheimer s disease, Parkinson s disease, Huntington s disease. Amyotrophic lateral sclerosis (ALS), multiple sclerosis, Friedreich s ataxia, and others (Crichton Ward 2006). Support comes from the observation that AD, PD, and many other neurodegenerative diseases are characterised by increased levels of some of these metal ions in specific regions of the brain. 

Importantly, the neuropathological and clinical characteristic features of MPTP-induced parkinsonism invariably resemble idiopathic Parkinson s disease rather more intimately than anyother previous human or experimented animal disorder exhibited by toxins, viruses, metals, or other modes. In short, the molecular pathophysiology of the ensuring MPTP neurotoxicity has virtually decephered the mystery surrounding the neurodegenerative mechanisms particularly associated with the idiopathic parkinsonism. 

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