The inflammatory cytokine interleukin-6 (IL-6) is increasingly expressed in the brain of aged mice. The heightened expression is due to increased binding of nuclear factor kappa B to the IL-6 gene promoter in microglial cells, which is triggered by an age-associated increase in oxidative stress. The chronic over expression of IL-6 as well as other inflammatory cytokines in the brains of older adults is thought to play a role in age-related changes in cognitive function and behavior and may predispose individuals to the onset of Alzheimer's disease. This is important for HIV-infected patients who now live longer due to the success of HAART therapy because the development of HIV-associated dementia (HAD) appears to involve the same cast of characters that are affected by normal aging. Therefore, the goal of this proposal is to investigate if neurocognitive complications associated with HIV disease are exacerbated by other neurophysiologic changes that occur during """"""""normal"""""""" aging. We propose three specific aims in an aged mouse model to address this issue. In the first aim, learning, memory, and motor skills in adult and aged mice will be assessed and oxidative stress and several inflammatory cytokines will be measured in the brain. Adult and aged mice will be treated with HIV-1 gp120 centrally via an indwelling intracerebroventricular (ICV) cannula to determine if aging might exacerbate oxidative stress and production of inflammatory cytokines in the brain of older adults with HIV disease. In the second aim we will compare learning, memory, and motor skills of adult and aged mice injected ICV with HIV-1 gpl20 or cytokines that are secreted by gpl20- stimulated microglia. Finally in the third aim we will reduce oxidative stress and inflammatory cytokines in the brain of aged mice to determine if this reduces the age-associated exacerbation of neurobehavioral deficits caused by HIV-1 gp 120 in the brain. We contend that this model using ICV injections of HIV-1 gpl20 and inflammatory cytokines is critically needed to understand not only the effects of aging on the neurocognitive complications associated with HIV disease, but also to provide insights into the interaction between HIV-induced pathophysiologies and Alzheimer's disease-related pathophysiologies that may be occurring. We have developed all of the techniques to successfully complete these objectives. This proposal addresses a critically important but as yet relatively unexplored area by carefully investigating how aging and HIV-1 gp120 interact in the brain to affect behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH069148-02
Application #
6770092
Study Section
Special Emphasis Panel (ZMH1-NRB-A (01))
Program Officer
Stoff, David M
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$340,436
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Jang, Saebyeol; Johnson, Rodney W (2010) Can consuming flavonoids restore old microglia to their youthful state? Nutr Rev 68:719-28
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Abraham, J; Jang, S; Godbout, J P et al. (2008) Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120. Neurobiol Aging 29:614-21
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Jang, Saebyeol; Kelley, Keith W; Johnson, Rodney W (2008) Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci U S A 105:7534-9

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