The goal of this application is to determine the impact of ovarian aging on neural inflammation. Several immune cell types are sensitive to gonadal steroids such as estrogen and the loss of these ovarian hormones at menopause significantly affects the immune system and the inflammatory response in target organs such as the brain, bone, skin and cardiovascular system. We are specifically interested in determining the effects of ovarian aging or reproductive senescence on the blood brain barrier and the neural inflammatory response. Inflammation is believed to contribute to the etiology of neurodegenerative diseases such as Alzheimer's and multiple sclerosis, and women as a group appear to be at a higher risk for these diseases. Ordinarily, the brain is protected from circulating immune cells and their cytotoxic products by the blood brain barrier. However, changes in the integrity of the blood brain barrier can exposed fragile, and often irreplaceable, neural networks to proteins that are fatal for them. ? ? Using an animal model of reproductive senescence, we have shown that the blood brain barrier of reproductive senescent females is more """"""""permissive"""""""" to intravenously injected dye as compared to young adult females. Furthermore, estrogen treatment increases dye transfer into a key brain region of the senescent brain, while suppressing dye transfer in young adult females. A similar dichotomy was seen in estrogen action in our forebrain injury studies, where estrogen suppressed inflammatory cytokine production in young females but exacerbated their levels in the senescent brain. Based on these studies, our central hypothesis is that ovarian aging increases the permeability of the blood brain barrier and increases cytotoxicity in the forebrain. This hypothesis will be tested in two Specific Aims: ? ? Specific Aim 1 will test the hypothesis that reproductive aging results in physical and functional changes in the blood brain barrier, causing this structure to become more permissive to circulating immune cells and proteins. Specifically, we will use fluorescent- and radio-labeled tracers to determine permeability of the blood brain barrier, and protein detection assays to determine changes in tight junction proteins, adherence proteins and matrix-cleaving enzymes of the blood brain barrier. ? ? Specific Aim 2 will test the hypothesis that systemic insults will result in a rapid and/or prolonged neural inflammation with greater neurodegeneration in reproductive senescent animals as compared to young adult animals. Two systemic insults will be used: an experimental sepsis model using LPS injections and a clinically-relevant inflammatory insult consisting of a high cholesterol diet. We will measure inflammatory mediators in peripheral organs (liver) and specific brain regions, leukocyte trafficking in the brain due to this systemic insult and neuronal cell death. ? ? ?
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