We have engineered a transgenic Caenorhabditis elegans model system that allows inducible expression of human beta amyloid peptide (Abeta1-42) in neuronal or muscle tissue. In both instances, Abeta accumulates intracellularly, forms amyloid, and results in cellular pathology. The goal of the proposed work is to understand the molecular and cellular basis of this toxicity, and to investigate how these processes might be involved in Alzheimer's disease pathology. The proposed project takes advantage of the experimental tools available in C. elegans, many of which are not available in other model systems. Specifically, we will use forward genetic screens to identify mutations that suppress Abeta toxicity, thereby identifying genes and gene products involved in transducing or combating this toxicity. The transgenic animals will also be used in microarray-based gene expression studies, allowing a molecular description of the initial cellular response to Abeta toxicity. The relationship between Abeta aggregation and toxicity will be investigated by the construction of additional transgenic lines expressing natural and engineered variant Abeta peptides. The role of specific genes and gene products in Abeta toxicity will be investigated using double-stranded RNA inhibition (RNAi) and Green Fluorescent Protein (GFP)-based transgenic reporter constructs.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Snyder, Stephen D
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University of Colorado at Boulder
Other Domestic Higher Education
United States
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Hassan, Wail M; Dostal, Vishantie; Huemann, Brady N et al. (2015) Identifying A?-specific pathogenic mechanisms using a nematode model of Alzheimer's disease. Neurobiol Aging 36:857-66
Machino, Kevin; Link, Christopher D; Wang, Susan et al. (2014) A semi-automated motion-tracking analysis of locomotion speed in the C. elegans transgenics overexpressing beta-amyloid in neurons. Front Genet 5:202
Muñoz-Lobato, Fernando; Rodríguez-Palero, María Jesús; Naranjo-Galindo, Francisco José et al. (2014) Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases. Antioxid Redox Signal 20:217-35
Lublin, Al; Link, Cd (2013) Alzheimer's Disease Drug Discovery: In-vivo screening using C. elegans as a model for ?-amyloid peptide-induced toxicity. Drug Discov Today Technol 10:e115-e119
McColl, Gawain; Roberts, Blaine R; Pukala, Tara L et al. (2012) Utility of an improved model of amyloid-beta (A?????) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease. Mol Neurodegener 7:57
Cotella, Diego; Hernandez-Enriquez, Berenice; Wu, Xilong et al. (2012) Toxic role of K+ channel oxidation in mammalian brain. J Neurosci 32:4133-44
Dostal, Vishantie; Roberts, Christine M; Link, Christopher D (2010) Genetic mechanisms of coffee extract protection in a Caenorhabditis elegans model of ?-amyloid peptide toxicity. Genetics 186:857-66
Dostal, Vishantie; Link, Christopher D (2010) Assaying ?-amyloid toxicity using a transgenic C. elegans model. J Vis Exp :
Park, Sang-Kyu; Link, Christopher D; Johnson, Thomas E (2010) Life-span extension by dietary restriction is mediated by NLP-7 signaling and coelomocyte endocytosis in C. elegans. FASEB J 24:383-92
McColl, Gawain; Rogers, Aric N; Alavez, Silvestre et al. (2010) Insulin-like signaling determines survival during stress via posttranscriptional mechanisms in C. elegans. Cell Metab 12:260-72

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