EXCEED THE SPACE PROVIDED. Apoptosis or programmed cell death contributes to neurotoxicity in numerous chronic neurodegenerative diseases. Oxidative stress is believed to be a principle factor. In Alzheimer's disease, for example, there is evidence for oxidative stress due to: 1) increased levels of aluminum, iron and mercury; 2) increased lipid peroxidation (generation of 4-hydroxynonenal); 3) reduced energy metabolism and less cytochrome c oxidase; 4) increased DNA and protein oxidation; and 5) increased generation reactive oxygen species by amyloid B (AB). Multiple transgenic models for Alzheimer's disease have been developed. Most involve the overexpression of various mutated forms of amyloid precursor protein resulting in increased AB secretion and plaque formation. The loss of neurons in these animal models, however, is conspicuously absent. Why are the neurons in the brains of these transgenic mice resistant to the effects of AB? These mice could be viewed not as a failed model for Alzheimer's disease but instead as a model for the prevention of the neuronal death associated with AB production, deposition and plaque formation. This proposal is designed to address this question in the Hsiao mice (Tg2576). Initial screens for changes in the prototypical antioxidant gene NAD(P)H:quinone oxidoreductase (NQO1) indicate that mRNA and protein for this gene are increased in Hsiao mice relative to littermate controls. Expression of NQO1 and numerous other protective genes can be increased by multiple mechanisms including oxidative stress through activation of the antioxidant response element (ARE). The observed changes in the Hsiao mice, therefore, may be due to ARE activation. Finally, pretreatment with tert-butylhydroquinone(tBHQ) decreases glutamate-, dopamine-, and H2O2- induced cytotoxicity (apoptosis) in rodent and human neuroblastoma cells. The protection afforded by tBHQ is attributed to the coordinate increase in ARE-driven genes. Cortical neuronal and astrocytic cultures fromARE- hPAP reporter mice indicate that tBHQ-mediated activation of the ARE occurs in both neurons and astrocytes. We hypothesize that increased expression of ARE-driven genes will block oxidative stress-induced cell death and contributes to the lack of neurotoxicity in the Hsiao mice.
The specific aims of this proposal are: 1) To determine the effect of overexpression of amyloid precursor protein on the ARE and antioxidant genes in neurons and glia; 2) To characterize the expression pattern and induction of antioxidant genes in neurons and glia of Nrf-2 null mice and determine if the lack of Nrf2 results in increased sensitivity to oxidative stress; 3) To determine the effect of overexpression of amyloid precursor protein on antioxidant gene expression, neuronal survival and plaque formation in Nrf-2 null mice. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008089-09
Application #
6830261
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Lawler, Cindy P
Project Start
1996-08-01
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
9
Fiscal Year
2005
Total Cost
$359,599
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Killoy, Kelby M; Harlan, Benjamin A; Pehar, Mariana et al. (2018) Decreased glutathione levels cause overt motor neuron degeneration in hSOD1WT over-expressing mice. Exp Neurol 302:129-135
Johnson, Delinda A; Johnson, Jeffrey A (2015) Nrf2--a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med 88:253-267
Joshi, Gururaj; Gan, Kok Ann; Johnson, Delinda A et al. (2015) Increased Alzheimer's disease-like pathology in the APP/ PS1?E9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging 36:664-79
Gan, Li; Johnson, Jeffrey A (2014) Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochim Biophys Acta 1842:1208-18
Pehar, Mariana; Beeson, Gyda; Beeson, Craig C et al. (2014) Mitochondria-targeted catalase reverts the neurotoxicity of hSOD1G?³A astrocytes without extending the survival of ALS-linked mutant hSOD1 mice. PLoS One 9:e103438
Fischedick, Justin T; Standiford, Miranda; Johnson, Delinda A et al. (2013) Structure activity relationship of phenolic diterpenes from Salvia officinalis as activators of the nuclear factor E2-related factor 2 pathway. Bioorg Med Chem 21:2618-22
Zhang, Linxia; Johnson, Delinda; Johnson, Jeffrey A (2013) Deletion of Nrf2 impairs functional recovery, reduces clearance of myelin debris and decreases axonal remyelination after peripheral nerve injury. Neurobiol Dis 54:329-38
Dowell, James A; Johnson, Jeffrey A (2013) Mechanisms of Nrf2 protection in astrocytes as identified by quantitative proteomics and siRNA screening. PLoS One 8:e70163
Vargas, Marcelo R; Burton, Neal C; Kutzke, Jennifer et al. (2013) Absence of Nrf2 or its selective overexpression in neurons and muscle does not affect survival in ALS-linked mutant hSOD1 mouse models. PLoS One 8:e56625
Joshi, Gururaj; Johnson, Jeffrey A (2012) The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. Recent Pat CNS Drug Discov 7:218-29

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