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

Abstract

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 non-specific responses to toxic aggregating proteins has not been made. We investigated alterations in gene expression induced by human β-amyloid peptide (Aβ) in a Caenorhabditis elegans Alzheimer’s disease model. Aβ-induced gene expression alterations were compared to those caused by a synthetic aggregating protein to identify Aβ-specific effects. Both Aβ-specific and non-specific alterations were observed. Among Aβ-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 Aβ and those induced by Cry5B, a bacterial pore-forming toxin. This led us to hypothesize that Aβ 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 Aβ-specific and non-specific mechanisms and provides potential targets for therapeutics discovery.

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

“…We therefore employed another C. elegans model in which transgenic GFP reporter worms were fed Escherichia coli engineered to secrete human Aβ (1-42) (52). C. elegans ingestion of Aβ-expressing E. coli leads to intestinal membrane damage, which can be measured by quantifying induced endosomes labeled with a GFP fusion protein that normally localizes to the intestinal lumen (52). This model allowed us to pre-expose Aβ to the peptides (by treating the E. coli cultures rather than the worms) before assaying Aβ toxicity.…”

In vivo induction of membrane damage by β-amyloid peptide oligomers

“…Unc-11 is orthologous to PICALM, another well-established late onset Alzheimer’s disease (LOAD) risk gene known to play a role in clathrin-mediated endocytosis [ 40 ]. clp-4 encodes one of nine C. elegans calpains, and we have previously noted that this specific calpain is upregulated both in a transgenic C. elegans model of Aβ toxicity [ 26 ] and in worms exposed to CRY5B [ 31 ]. The CLP-4 calpain also activates the C. elegans CDK5 ortholog via cleavage of p35 to p25 [ 58 ], and thus has functions analogous to human calpains 1/2, which are required for Aβ-induced tau phosphorylation via p25 activation of CDK5 [ 50 , 81 ].…”

Phospholipase D functional ablation has a protective effect in an Alzheimer’s disease Caenorhabditis elegans model

“…Interestingly, in an unbiased gene expression study, it was observed in another C . elegans strain expressing human Aβ that the toxic peptide leads to gene expression changes that overlap with changes induced by the membrane pore-inducing toxin, Cry5B 39 , suggesting that membrane damage mechanisms could be important pathways induced by Aβ. In fact, PLD has been shown to be involved in membrane damage pathways 40 .…”