Aging Vulnerability to Inflammatory Processes

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DESCRIPTION (provided by applicant): An important questions in research on Alzheimer's Disease (AD) is to define why specific brain regions and neural systems are affected with the progression of the symptoms of dementia and to determine what mechanisms will slow the progression of these processes. This proposal is a continuation of my previous studies aimed at understanding the role of neuro-inflammation in the degeneration of the AD brain. The degeneration or dysfunction of the temporal lobe and forebrain cholinergic neurons are responsible for aspects of the dementia associated with AD and my preliminary studies indicate that temporal lobe and basal forebrain acetylcholine neurons are selectively vulnerable to the neurotoxic effects of chronic neuroinflammation. The current series of studies will examine the effects of chronic neuroinflammation within the brain of four different types of mice: 1) non-transgenic control mice, or transgenic mice that express either, 2) the Swedish mutant amyloid precursor protein, APP (Tg2576; K670N/M671L; Hsiao, et al., 1996), 3) the mutant presenilin type1 (PS1 line 5.1; M146L; Duff, et al, 1996) gene or, 4) both genes simultaneously. The Alzheimer's-like phenotype present in these mice has already been well characterized. The proposed specific aims will test the overall hypothesis that inflammatory proteins influence the pathophysiological processes that underlie the degeneration of neurons in brains of people with AD. I further predict that the extent of pathology induced by the chronic neuroinflammation will be exacerbated in the combined presence of the Beta-amyloid and PS1 mutations. In the present proposal, the biochemical, pathological and behavioral consequences of chronic neuroinflammation produced by the infusion of Iipopolysaccharide (LPS). LPS is a component of the cell wall of gram-negative bacteria and has been used experimentally to stimulate the production of the endogenous cytokines and other inflammatory proteins. Our preliminary studies using LPS infusion into the 4th ventricle, found that the greatest inflammatory response was contained within the basal forebrain, hippocampus, particularly the dentate gyrus, as well as within the entorhinal and piriforin cortexes. The proposed studies will explore the hypothesis that inflammatory processes are involved in the initial stages of cellular and molecular dysfunction that may alter cellular vulnerability and that these changes may in turn lead to cell death and cognitive impairments. In addition, these studies will investigate whether there is an age-associated increase in the vulnerability to these processes. Finally, because the cascade of biochemical processes that leads to neuronal degeneration may involve the production of prostaglandins the proposed studies will also investigate whether it is possible to antagonize these processes and provide neuroprotection. Once accomplished, the research will significantly enhance our understanding of the role of inflammation in neurodegeneration in the AD brain and will greatly improve my ability to reproduce, and then manipulate with potential pharmacotherapies, important steps in the degeneration of neurons in the brain of AD patients.