Although there is compelling evidence that the ?-amyloid peptide (A?) is centrally involved in Alzheimer's disease pathology, the mechanisms of A? toxicity and its specific targets remain unresolved. This project is a continuation of our studies using the intensely studied nematode worm Caenorhabditis elegans as a model to investigate the basis of (human) A? toxicity. We have previously shown that transgenic worms engineered to express human A? 1-42, replicate some aspects of Alzheimer's disease pathology. By a combination of molecular and genetic approaches, we have now identified a set of conserved genes that modulate A? toxicity in these transgenic worm models. In addition, analysis of transgenic worms expressing single amino acid variants has led to the identification of an A? variant that is substantially non-toxic in vivo. The goal of this proposal is to synthesize these findings to establish: 1) the identity of the toxic A? species, 2) the cellular pathways that influence the formation of the toxic species, and 3) the specific cellular targets of A?.
The Specific Aims of this proposal are to: 1) perform an in vivo structure/function analysis of A? toxicity by constructing and characterizing transgenic worms expressing variant A? peptides. These studies will directly test the """"""""toxic A? oligomer"""""""" model, 2) determine the molecular mechanisms by which evolutionarily conserved modifier genes alter A? toxicity, and 3) validate the proposed mechanisms for both A? toxicity and the protective genes we have identified using mammalian cell culture and primary neuronal cultures. Our proposed studies have direct relevance for the diagnosis and treatment of Alzheimer's disease. The identity of the key toxic form(s) of A? may be critical for designing drugs that prevent its formation or toxic activity. Characterization of genes that affect the toxicity of A? may be important for both risk assessment and the development of effective interventions for Alzheimer's and other neurodegenerative diseases. PUBLIC HEALTH REVELANCE: There is compelling evidence that accumulation of a specific protein, the ?- amyloid peptide, underlies the brain pathology found in Alzheimer's disease, which affects ~5,000,000 people in the US. The proposed study seeks to determine the cellular and molecular basis of ?-amyloid peptide toxicity. Understanding the toxic mechanism of this protein make be critical for developing therapeutics for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG012423-12
Application #
7612077
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Refolo, Lorenzo
Project Start
1996-09-01
Project End
2013-03-31
Budget Start
2009-04-15
Budget End
2010-03-31
Support Year
12
Fiscal Year
2009
Total Cost
$317,179
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
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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