title: 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 nonspecific responses to toxic aggregating proteins has not been made. We investigated alterations in gene expression induced by human beta-amyloid peptide (Aβ) in a Caenorhabditis elegans AD model. Aβ-induced gene expression alterations were compared with those caused by a synthetic aggregating protein to identify Aβ-specific effects. Both Aβ-specific and nonspecific 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 nonspecific mechanisms and provides potential targets for therapeutics discovery.
authors.affiliation: Department of Biomedical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, USA; Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA. Electronic address: hassanw@uwm.edu.
authors.forename: Wail M
authors.initials: WM
authors.lastname: Hassan
authors.affiliation: Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA.
authors.forename: Vishantie
authors.initials: V
authors.lastname: Dostal
authors.affiliation: Department of Biomedical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
authors.forename: Brady N
authors.initials: BN
authors.lastname: Huemann
authors.affiliation: Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Yerg
authors.affiliation: Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Link
mesh_terms: D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D000083722:Bacillus thuringiensis Toxins; D001426:Bacterial Proteins; D017173:Caenorhabditis elegans; D004195:Disease Models, Animal; D004731:Endotoxins; D015870:Gene Expression / Q000235:genetics*; D006460:Hemolysin Proteins; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D058990:Molecular Targeted Therapy; D046988:Proteasome Endopeptidase Complex / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D000083722:Bacillus thuringiensis Toxins; D001426:Bacterial Proteins; D004731:Endotoxins; D006460:Hemolysin Proteins; C030956:insecticidal crystal protein, Bacillus Thuringiensis; D046988:Proteasome Endopeptidase Complex
keywords: Alzheimer's disease; Beta-amyloid; Dementia; Neurodegeneration; Neurodegenerative disorders