The Caenorhabditis elegans Aβ1-42 model of Alzheimer disease predominantly Expresses Aβ 3-42

Abstract

Transgenic expression of human amyloid β (Aβ) peptide in body wall muscle cells of Caenorhabditis elegans has been used to better understand aspects of Alzheimer disease (AD). In human aging and AD, Aβ undergoes post-translational changes including covalent modifications, truncations, and oligomerization. Amino truncated Aβ is increasingly recognized as potentially contributing to AD pathogenesis. Here we describe surface- enhanced laser desorption ionization-time of flight mass spectrometry mass spectrometry of Aβ peptide in established transgenic C. elegans lines. Surprisingly, the Aβ being expressed is not full-length 1-42 (amino acids) as expected but rather a 3-42 truncation product. In vitro analysis demonstrates that Aβ3-42 self-aggregates like Aβ 1-42, but more rapidly, and forms fibrillar structures. Similarly, Aβ3-42 is also the more potent initiator of Aβ1-40 aggregation. Seeded aggregation via Aβ 3-42 is further enhanced via co-incubation with the transition metal Cu(II). Although unexpected, the C. elegans model of Aβ expression can now be co-opted to study the proteotoxic effects and processing of Aβ3-42. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.