Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

Abstract

Amyloid plaques consisting of aggregated Ab peptide are a hallmark of Alzheimer's disease. Among the different forms of Ab, the one of 42aa length (Ab42) is most aggregationprone and also the most neurotoxic. We find that eye-specific expression of human Ab42 in Drosophila results in a degeneration of eye structures that progresses with age. Dietary supplements of zinc or copper ions exacerbate eye damage. Positive effects are seen with zinc/copper chelators, or with elevated expression of MTF-1, a transcription factor with a key role in metal homeostasis and detoxification, or with human or fly transgenes encoding metallothioneins, metal scavenger proteins. These results show that a tight control of zinc and copper availability can minimize cellular damage associated with Ab42 expression.

The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

“…It has been found that a Cu 2+ /Zn 2+ chelator, PBT2, decreases soluble Aβ levels and improves cognition in Alzheimer's disease transgenic mice [24], and in another study, it has been found that for two transgenic mouse models of Alzheimer's disease (Tg2576 and TgCRND8), a Zn 2+ enriched diet is associated with potentiated Alzheimer's-like spatial memory impairment, as well as a reduction in Aβ plaque deposition, potentially increasing soluble toxic Aβ levels [25]. Furthermore, in drosophila models of Alzheimer's disease, tight control of copper and zinc availability reduces disease phenotypes [26].…”

Drosophila melanogaster as a model organism for Alzheimer’s disease

“…Drosophila models for AD proved to be a useful tool to investigate the influence of different metal ions on Aβ-induced neurodegeneration [57-61]. By feeding Aβ42 expressing flies with copper or zinc supplemented food the Aβ42-induced phenotypes such as REP decreased survival and locomotor defects were enhanced.…”

“…By feeding Aβ42 expressing flies with copper or zinc supplemented food the Aβ42-induced phenotypes such as REP decreased survival and locomotor defects were enhanced. In contrast, food supplemented with metal-chelating substances suppressed these phenotypes [57]. Genetic manipulation of metal homeostasis further underlined the role of zinc and copper levels in Aβ42-induced toxicity [57-59].…”

Energy metabolism, proteotoxic stress and age-related dysfunction – Protection by carnosine

“…In these cases the explanations of toxicity is uncertain, although stimulation of reactive oxygen species (ROS) generation is frequently suggested (Sayre et al, 2008). Some altered proteins are thought to promote ROS formation following associated with multivalent metal ions such as copper and iron (Hua et al, 2011). Another possibility is spontaneous interaction of an altered polypeptide chain with mitochondrial outer membrane in such as way that compromises organelle function; induction of mitochondrial dysfunction is a likely major cause of ageing (Aliev et al, 2009).…”