Intracellular amyloid formation in muscle cells of A-transgenic Caenorhabditis elegans: Determinants and physiological role in copper detoxification

Background: The amyloid -peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine A aggregation in vivo are poorly understood, as well as the cellular meaning of this process itself. Genetic data as well as cell biological and biochemical evidence strongly support the hypothesis that A is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that A is involved in Inclusion Body Myositis, a common myopathy of the elderly in which the peptide accumulates intracellularly. Results: In the present work, we found that intracellular A aggregation in muscle cells of Caenorhabditis elegans overexpressing A peptide is affected by two single amino acid substitutions, E22G (Arctic) and V18A (NIC). Both variations show decrease intracellular amyloidogenesis compared to wild type A. We show that intracellular amyloid aggregation of wild type A is accelerated by Cu²⁺ and diminished by copper chelators. Moreover, we demonstrate through toxicity and behavioral assays that A-transgenic worms display a higher tolerance to Cu²⁺ toxic effects and that this resistance may be linked to the formation of amyloid aggregates. Conclusion: Our data show that intracellular A amyloid aggregates may trap excess of free Cu²⁺ buffering its cytotoxic effects and that accelerated intracellular A aggregation may be part of a cell protective mechanism.