Metals in Alzheimer's and Parkinson's Diseases
Section snippets
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.
References (74)
Metals and neuroscience
Curr Opin Chem Biol
(2000)- et al.
An iron-responsive element type II in the 5’ untranslated region of the Alzheimer's amyloid precursor protein transcript
J Biol Chem
(2002) - et al.
Zinc-specific autometallographic in vivo selenium methods: tracing of zinc-enriched (ZEN) terminals, ZEN pathways, and pools of zinc ions in a multitude of other ZEN cells
J Histochem Cytochem
(2005) - et al.
Correlation of R2 with total iron concentration in the brains of rhesus monkeys
J Magn Reson Imaging
(2005) - et al.
Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex
Redox Rep
(2005) - et al.
Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation
Brain
(2007) - et al.
Metalloenzyme-like activity of Alzheimer's disease β-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol and biological reducing agents to neurotoxic H2O2
J Biol Chem
(2002) - et al.
Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia
Acta Neuropathol (Berl)
(1990) - et al.
Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics
Eur J Pharmacol
(2006) - et al.
Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice
Proc Natl Acad Sci U S A
(2002)