Chronic neuroinflammation is a prominent feature of Alzheimer's disease (AD) and is believed to contribute to the molecular cascade that ultimately manifests as cognitive dysfunction. Although glial activation is influenced by neuronal plaques and tangles, its presence in the aged brain, independent of AD-like neuropathology, suggests that chronic neuroinflammation may be an initial component of, and factor in age-related dementia. Furthermore, epidemiological studies suggest that non-steroidal anti-inflammatory drug (NSAID) treatment initiated prior to display of clinical symptoms may be effective in delaying the onset of cognitive impairments in persons at-risk for AD. One key player that is believed to drive this neuroinflammatory process is lnterleukin (IL)-1beta, a pro-inflammatory cytokine that is upregulated in AD brain and other neurodegenerative disorders. We have found that intracerebral administration of IIL-1beta in mouse brain induces a robust glial response and increased expression of cyclooxygenase (COX)-2, an isoform lot the enzyme responsible for prostaglandin synthesis and the target of NSAIDs. Also, we have found a sustaining 'inflammatory response following chronic intracerebroventricular (i.c.v.) infusion of IL-1beta. Although substantial research has been conducted in rat models of chronic neuroinflammation and transgenic mouse models of AD neuropathology, data are sparse for the effect of prolonged glial activation and elevated IL-1beta brain concentrations on adult mouse behavior. Furthermore, the issue of sex-specific responses to a sustained pro-inflammatory stimulus has yet to be addressed. To investigate the hypothesis that chronic neuroinflammation contributes to cognitive dysfunction in mice, we propose two aims. In the first aim, we will establish the behavioral consequence of chronic i.c.v. lL- 1beta infusion on spatial and non-spatial memory. Male and female mice will be used to determine potential sex-difference in IL-1beta - induced mnemonic deficits. In the second aim, immunohistochemical analysis of glial activation, cyclooxygenase expression and markers of cholinergic activity will be conducted on neural tissue from the behaviorally-tested animals to correlate molecular indices of inflammation with behavioral performance. These results will be beneficial for future studies on prevention/treatment of inflammation-induced memory dysfunction utilizing NSAIDS. Together these studies will characterize a mouse model that will elucidate the role of chronic neuroinflammation in the pathobiology and cognitive decline associated with aging and AD.
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|Guzmán, Cristina B; Graham, Kaylan A; Grace, Lindsey A et al. (2009) Sex-dependent effect of cyclooxygenase-2 inhibition on mouse spatial memory. Behav Brain Res 199:355-9|