Acute cognitive impairment is common in elderly emergency department patients and frequently results from infections that are unrelated to the CNS. Cognitive impairment leads to a failure in self-care and is associated with increased hospitalization and delayed recovery. Preliminary data presented in this application indicate that normal aging is associated with increased neuroinflammation and that an exaggerated inflammatory response occurs in the brain of healthy aged mice when lipopolysaccharide (LPS) activates the peripheral innate immune system. We believe that this phenomenon may underlie the cognitive deficits that are highly prevalent in elderly patients and explain why infection is a risk factor for development of neurodegenerative diseases. In this application, we will directly test the hypothesis that activation of the peripheral innate immune system produces an exaggerated inflammatory response in the aged brain that causes severe and prolonged deficits in cognitive function and changes in hippocampal pyramidal neuron morphology. We propose four specific aims in an aged mouse model to address the hypothesis. To determine if inflammation in the brain of older adults with a systemic infection is exacerbated, in the first aim adult and aged mice will be given LPS i.p. and inflammatory cytokines will be measured in hippocampal tissue obtained using laser capture microdissection techniques, and cytokine-positive microglia will be localized by immunohistochemical staining. Special attention will be paid to the hippocampus because it is sensitive to aging and involved in cognitive disorders that are evident in elderly patients with systemic infections.
The second aim will determine the behavioral consequences of the exaggerated inflammatory response in aged mice by assessing their performance in several hippocampal-dependent tests;
and aim three will explore the root of the behavioral changes by determining the effects of LPS and recombinant cytokines on hippocampal pyramidal neuron morphology. Finally in the fourth aim we will inhibit inflammatory cytokines in the brain of aged mice that are challenged with LPS to determine if this inhibits the age-associated exacerbation of neurobehavioral deficits and indications of diminished neuronal circuitry. One of the major conundrums in the current literature is that behavioral deficits persist in the elderly long after the infection has been resolved and cytokines returned to normal. Therefore, we contend that understanding the effects of inflammatory cytokines on morphology of neurons in brain areas that mediate cognitive behavior is critical. A better understanding of how aging influences the neurobehavioral complications associated with systemic infections is needed to improve the likelihood for """"""""successful"""""""" aging.
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