Metals in Alzheimer's and Parkinson's Diseases

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There has been steadily growing interest in the participation of metal ions (especially, zinc, copper, and iron) in neurobiological processes, such as the regulation of synaptic transmission. Recent descriptions of the release of zinc and copper in the cortical glutamatergic synpase, and influencing the response of the NMDA receptor underscore the relevance of understanding the inorganic milieu of the synapse to neuroscience. Additionally, major neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, are characterized by elevated tissue iron, and miscompartmentalization of copper and zinc (e.g. accumulation in amyloid). Increasingly sophisticated medicinal chemistry approaches, which correct these metal abnormalities without causing systemic disturbance of these essential minerals, are being tested. These small molecules show promise of being disease-modifying.

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Metal ions, aging, and neurodegenerative diseases

The field of metals in neuroscience has expanded extraordinarily since we reviewed it in 2000 [1]. As an illustration, performing a search of keywords ‘zinc’ and ‘copper’ and ‘Alzheimer's disease’ since 1984 (when the sequence of β-amyloid was first reported), indicates a linear increase in the publications per year containing these key words expressed as a proportion of total publications containing ‘Alzheimer's disease’ (Figure 1). Although neuroscientists have traditionally shunned it, it is

Alzheimer's disease

AD is characterized by the deposition of amyloid plaques, the major constituent being the amyloid-β peptide (Aβ) that is cleaved from the membrane-bound amyloid precursor protein (APP). Although the function of APP is unknown recent evidence suggests it has a role to play in maintaining copper homeostasis (reviewed [12, 19]).

Iron is concentrated within the vicinity of amyloid plaques in both humans (reviewed in [18]) and APP transgenic mice [20], where it is visualized as a negative signal on

Physiological interactions of APP and its processing with zinc and copper

APP coordinates Cu+ at its amino-terminus, and APP expression promotes the export of neuronal copper [57]. A functional role for APP in copper homeostasis is supported by reports that cellular Cu drives the expression of APP mRNA [58, 59].

BACE1 (beta-secretase) possesses a Cu+-binding site in its C-terminal cytoplasmic domain through which it interacts with domain 1 of the copper chaperone of SOD1 (CCS1) [60]. The functional implications of this interaction are unknown but imply that copper

Parkinson's disease

Zinc and iron are increased and copper is decreased in the substantia nigra (SN) in Parkinson's disease (PD). The mechanisms of these changes are not well understood but the elevation of iron in particular may contribute to oxidative stress and loss of dopaminergic neurons of the SN as well as the deposition of intracellular inclusion bodies (Lewy bodies), both characteristic features of PD. The importance of iron in fomenting PD pathology is supported by results showing that both iron

Conclusions

There has been an acceleration in our appreciation for the presence and relevance of metal ions, especially zinc, copper, and iron, in synaptic architecture and dysregulation of the inorganic milieu of the brain in the etiopathogenesis of major neurodegenerative disorders. The importance of these findings may become apparent soon with the testing of potentially disease-modifying drugs that target this sophisticated new neurochemistry.

Disclosures

The authors are paid consultants for and shareholders in Prana Biotechnology Ltd.

References and recommended reading

Papers of particular interest, published within the annual period of the review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work is supported with funds from the National Health and Medical Research Council of Australia, and The Australian Research Council.

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