Research article

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

Alicia N Minniti¹ , Daniela L Rebolledo¹ , Paula M Grez¹ , Ricardo Fadic² , Rebeca Aldunate¹ , Irene Volitakis³ , Robert A Cherny³ , Carlos Opazo⁴ , Colin Masters³ , Ashley I Bush^3,5 and Nibaldo C Inestrosa¹

¹  Centro de Regulación Celular y Patología "Joaquín V. Luco" (CRCP), MIFAB, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331010 Santiago, Chile

²  Departamento de Neurología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

³  Oxidation Disorders Laboratory, Mental Health Research Institute of Victoria and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia

⁴  Laboratorio de Neurobiometales, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Chile

⁵  Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA

author email corresponding author email

Molecular Neurodegeneration 2009, 4:2doi:10.1186/1750-1326-4-2

Published:	6 January 2009

Abstract

Background

The amyloid β-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 Aβ 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 Aβ is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that Aβ 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 Aβ aggregation in muscle cells of Caenorhabditis elegans overexpressing Aβ peptide is affected by two single amino acid substitutions, E22G (Arctic) and V18A (NIC). Both variations show decrease intracellular amyloidogenesis compared to wild type Aβ. We show that intracellular amyloid aggregation of wild type Aβ is accelerated by Cu²⁺ and diminished by copper chelators. Moreover, we demonstrate through toxicity and behavioral assays that Aβ-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 Aβ amyloid aggregates may trap excess of free Cu²⁺ buffering its cytotoxic effects and that accelerated intracellular Aβ aggregation may be part of a cell protective mechanism.