The goal of this project is to understand the cellular and molecular basis of beta-amyloid peptide (Abeta) toxicity. This peptide is deposited as insoluble amyloid aggregates in the senile plaques found in the brains of Alzheimer's Disease (AD) patients, and is believed to be central to the pathology of this disease. A novel AD model system will be employed in which of the intensely studied nematode worm, Caenorhabditis elegans, is engineered to express human Abeta peptide. These transgenic animals express high levels of the Abeta peptide, which rapidly leads to the formation of amyloid deposits and associated toxic effects. This model system will be used to investigate the relationships between Abeta structure, aggregation, and toxicity by the construction of transgenic animals expressing wild-type and variant Abeta containing single or multiple amino acid substitutions. These animals will be assayed for amyloid formation and known markers of Abeta toxicity, such as oxidative damage to proteins. Characterization of these animals will also include examination of the complete Abeta-dependent gene expression profile, assayed by mRNA hybridization to DNA microarrays that contain probes for the vast majority of C. elegans genes. The genetic accessibility of this model organism will also allow the identification of genes directly involved in Abeta toxicity, by the isolation and characterization of mutations that suppress the toxic effects of the Abeta peptide.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG012423-06S1
Application #
6487825
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Snyder, D Stephen
Project Start
1996-09-01
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2003-08-31
Support Year
6
Fiscal Year
2001
Total Cost
$71,503
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
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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