There are currently no effective cures or treatments for chronic CNS conditions such as Alzheimer's disease (AD) and stroke. We and others have shown that the activation of lipoxygenases (LOXs) play a central role in the nerve cell death associated with both disorders because LOX inhibitors reduce nerve cell death in both cell culture studies and in animal models that mimic these disorders. Furthermore, LOXs are highly elevated in AD and mild cognitive impairment, and AD transgenic animals in which the various LOXs and the phospholipases that provide LOX substrates are genetically deleted have greatly reduced pathology. However, the molecular mechanisms by which LOX enzymes are activated and how their products cause nerve cell death are unknown. Nor have CNS therapies based upon LOX metabolism been extensively tested in animal models. To understand the signaling pathways and gain better insight into potential therapeutic targets, we will study LOX-mediated nerve cell death in two robust cell culture models of chronic oxidative stress and intracellular beta amyloid toxicity. Both paradigms are associated with the depletion of glutathione and ROS production. In addition, LOX inhibitors enhance the removal of aggregated protein, a condition associated with AD and aging in general. Using these experimental systems, we will answer the following questions. What is the mechanism by which the depletion of glutathione activates LOXs and how do the LOX metabolites stimulate ROS production from mitochondria? What are the specific LOX products involved in both ROS production and the cell death pathways? What are the molecular signaling pathways involved? How does the inhibition of LOX enzymatic activity increase the rate of clearance of aggregated intracellular amyloid and promote cell survival? Finally, we will determine if our best pan-LOX inhibitor is able to clear intracellular A?, reduce AD pathology and behavioral deficits in a transgenic mouse AD model and define the contribution of the major LOX genes to AD pathology. These experiments will build a solid foundation for the role of LOX metabolism in nerve cell death and the metabolism of intracellular amyloid, test this pathway in animals, and identify new therapeutic targets.

Public Health Relevance

There are no cures or effective treatments for Alzheimer's disease or stroke, nor is it understood how and why nerve cells die in these conditions. On the basis of a very rigorous screening procedure we have identified a series of drug-like small molecules that are effective in animal models of Alzheimer's and stroke, but we do not understand the molecular pathways by which they are neuroprotective. To push these drugs to the clinic and to identify more and perhaps better therapeutic targets, we need to understand exactly how these drugs function, and that is the goal of this proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG035055-03
Application #
8290360
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Wise, Bradley C
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$375,373
Indirect Cost
$178,327
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Currais, Antonio; Prior, Marguerite; Dargusch, Richard et al. (2014) Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice. Aging Cell 13:379-90
Prior, Marguerite; Chiruta, Chandramouli; Currais, Antonio et al. (2014) Back to the future with phenotypic screening. ACS Chem Neurosci 5:503-13
Valera, Elvira; Dargusch, Richard; Maher, Pamela A et al. (2013) Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease. J Neurosci 33:10512-25
Prior, Marguerite; Dargusch, Richard; Ehren, Jennifer L et al. (2013) The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice. Alzheimers Res Ther 5:25
Chen, Qi; Prior, Marguerite; Dargusch, Richard et al. (2011) A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease. PLoS One 6:e27865