Identifying A-specific pathogenic mechanisms using a nematode model of Alzheimer's disease.

Multiple gene expression alterations have been linked to Alzheimer's disease (AD), implicating multiple metabolic pathways in its pathogenesis. However, a clear distinction between AD-specific gene expression changes and those resulting from nonspecific responses to toxic aggregating proteins has not been made. We investigated alterations in gene expression induced by human beta-amyloid peptide (A) in a Caenorhabditis elegans AD model. A-induced gene expression alterations were compared with those caused by a synthetic aggregating protein to identify A-specific effects. Both A-specific and nonspecific alterations were observed. Among A-specific genes were those involved in aging, proteasome function, and mitochondrial function. An intriguing observation was the significant overlap between gene expression changes induced by A and those induced by Cry5B, a bacterial pore-forming toxin. This led us to hypothesize that A exerts its toxic effect, at least in part, by causing damage to biological membranes. We provide in vivo evidence consistent with this hypothesis. This study distinguishes between A-specific and nonspecific mechanisms and provides potential targets for therapeutics discovery.