Iron, copper, and iron regulatory protein 2 in Alzheimer's disease and related dementias

Abstract

Accumulating evidence implicates a role for altered iron and copper metabolism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, imbalances in the levels of the various forms of iron at different stages of AD have not been examined. In this pilot study we extracted and measured the levels of loosely bound, non-heme and total iron and copper in the frontal cortex and hippocampus of patients with mild-moderate AD (n=3), severe AD (n=8) and dementia with Lewy bodies (DLB, n=6), using graphite furnace atomic absorption spectrometry (GFAAS). Additionally, the expression of iron regulatory protein 2 (IRP2) was examined in relation to the pathological hallmarks of AD and DLB, amyloid plaques, neurofibrillary tangles (NFT), and Lewy bodies, by immunohistochemistry. We found significantly decreased loosely bound iron in the hippocampal white matter of mild-moderate and severe AD patients and a trend towards increased non-heme iron in the hippocampal gray matter of severe AD patients. Furthermore, decreased levels of total copper were seen in severe AD and DLB frontal cortex compared to controls, suggesting an imbalance in brain metal levels in both AD and DLB. The decrease in loosely bound iron in mild-moderate AD patients may be associated with myelin breakdown seen in the beginning stages of AD and implicates that iron dysregulation is an early event in AD pathogenesis.

Paradoxical Condensation of Copper with Elevated β-Amyloid in Lipid Rafts under Cellular Copper Deficiency Conditions

“…Our current data indicate that lipid rafts provide a favorable environment for the co-enrichment of copper and A␤, especially under conditions of copper deficiency. We hypothesize that in aging and AD, where there is intracellular copper deficiency (5,6,69), the concomitant enrichment of A␤ and copper within lipid rafts promotes the formation of redoxactive A␤⅐Cu 2ϩ complexes, fostering the catalytic oxidation of cholesterol, lipid, and the generation of neurotoxic H 2 O 2 . This further creates a vulnerable environment for A␤ to cross-link, forming SDS-resistant oligomers characteristic of A␤ extracted from AD brains (67,68).…”

The use of multi-target drugs in the treatment of neurodegenerative diseases

“…Many DLB subjects have dementia and depression resulting from possible degeneration of cholinergic, noradrenergic and serotonergic neurons. In both AD and DLB, accumulation of iron is found inside some melanin-containing dopaminergic neurons and inside amyloid plaques and neurofibrillary tangles [40]. It has been suggested that iron accumulation may contribute to the oxidative stress-induced apoptosis reported in both diseases [41].…”

Copper Promotes the Trafficking of the Amyloid Precursor Protein

“…In addition, A␤ is able to catalyze the reduction of Cu(II) and Fe(III), generating reactive oxygen species that contribute to the oxidative stress observed in the AD brain (8 -14). Paradoxically, there is evidence of copper deficiency in neighboring cells (15)(16)(17)(18), compromising the activity of copper-dependent enzymes, such as cytochrome c-oxidase and copper/zinc-superoxide dismutase (SOD1), which are essential for cellular respiration and as antioxidant defense, respectively (19 -21). Restoration of copper balance using ionophores (22), such as clioquionol and PBT-2, has shown promising results in both animal and human trials (23)(24)(25)(26).…”