Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that affects more than 5 million people in the United States. This number is a 10 percent increase from the previous estimate of 4.5 million and is projected to sharply increase to 8 million by 2030. At present, the few agents that are FDA- approved for treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. In this project we postulate a new target for therapeutic intervention in AD, the activated/altered vascular endothelium. Work from our laboratory has demonstrated a dysfunctional cerebral microcirculation in AD characterized by the upregulation of numerous inflammatory proteins and neurotoxic factors. Many of these vascular-derived factors are directly injurious to or lethal for neurons. Vascular-derived factors can also injure neurons indirectly by activating neighboring glial cells which in turn release reactive oxygen species and inflammatory factors thus propagating deleterious neuroinflammation. The "activated" brain vasculature represents an important and unexplored source of neurotoxins in the AD brain. It is our hypothesis that pharmacologic interventions aimed at reducing vascular activation and release of neurotoxins will improve cognitive function in AD. If the notion that vascular-derived factors contribute to a cascade of events in the AD brain that lead to dementia then blocking or decreasing vascular activation, and the subsequent release of neurotoxic factors, should improve cognitive performance. This hypothesis is novel, testable and supported by preliminary data. To test this hypothesis we propose the following Specific Aim: To determine whether pharmacologic interventions aimed at reducing vascular activation and release of neurotoxins improve cognitive function in an animal model of AD. Transgenic AD mice receive drugs beginning at 2 or 10 months of age and continuing for 6 months. The performance of cognitive tasks is compared between AD mice and drug-treated AD mice to determine whether administration of drug alters the onset and/or severity of cognitive decline. Cognitive function is assessed using radial arm and watermaze behavioral assays. In addition, expression of neurotoxic and inflammatory proteins is determined in the blood and CSF by ELISA and in the cerebrovasculature by immunostaining. Data demonstrating a causal link between the activated vascular phenotype and cognitive impairment could provide valuable new insights into the development of AD. Furthermore, because several vascular activation inhibitor drugs are currently FDA approved or in use in Phase III clinical trials for cancer treatment, new clinical trials with these drugs could be rapidly designed and implemented in AD patients.

Public Health Relevance

New therapeutic approaches for Alzheimer's disease (AD) are desperately needed. In this project we propose brain blood vessels as new targets for therapeutic intervention in AD. Data demonstrating a causal link between the activated vascular phenotype and cognitive impairment could provide valuable new insights into the development of AD. Furthermore, because several activation inhibitor drugs are currently FDA approved or in use in Phase III clinical trials for cancer treatment, new clinical trials with these drugs could b rapidly designed and implemented in AD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG040718-01A1
Application #
8293818
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (56))
Program Officer
Petanceska, Suzana
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$222,750
Indirect Cost
$72,750
Name
Texas Tech University
Department
None
Type
Schools of Medicine
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430