Aging Oxidative Stress and Microglia

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DESCRIPTION (provided by applicant): Statement of the Problem: In recent years, extensive evidence has shown that inflammation develops in the brain during aging and may be the underlying factor for the development of declines in synaptic plasticity in the CNS and neurodegenerative disease. However, the causes and consequences of specific brain inflammatory responses are still not well understood. We have found that amelioration of brain inflammation with various treatments has beneficial actions on several indicators of impaired synaptic plasticity. However, it appears that the more advanced the inflammatory process becomes, the more difficult it is to reverse its effects. This proposal is aimed at targeting early dysregulating events that activate brain inflammatory pathways to test the hypothesis that learning can be protected during aging by early intervention against inflammation. In the current funding period we have demonstrated that inducing inflammation in the cerebellum by infusing TNF1 disrupts cerebellar synaptic plasticity (motor learning) in young rats while blocking TNF1 in aged rats modestly improves motor learning. Microglial cells are an important source of reactive oxygen species (ROS) in the brain as well as other inflammatory signals such as pro-inflammatory cytokines such as TNF1 and therefore may play a role in modulating CNS oxidative stress and neurodegenerative diseases. We have recent evidence that key regulators of communication between neurons and microglia are disrupted in the aged brain and may be one of the factors that precedes and initiates the observed increase in TNF1 and a chronic inflammatory state. We plan to investigate the role of these neuronal-glial communication regulators as part of this ongoing project. A major focus of these studies is to examine the hypothesis that disruption of key modulators of neuronal-glial communication will lead to an aging phenotype. We will examine two possible regulators of communication between neurons and glia, fractalkine and CD200. The second aim is to investigate the hypothesis that replacement of key modulators in the aged brain will re-instate a young phenotype. To examine this question we will administer fractalkine (an anti-inflammatory chemokine) or CD200 (an anti-inflammatory immunoglobulin) into the cerebellum of aged rats and they will be tested for performance on a cerebellar learning task that we have demonstrated is sensitive to changes in inflammation, delay eyeblink conditioning. The third aim examines the hypothesis that replacement of key modulators in the aged brain will re-instate a young phenotype. We will administer fractalkine or CD200 into the hippocampus and examines cognitive function and LTP as indexes of synaptic plasticity in the hippocampus. PUBLIC HEALTH RELEVANCE: In recent years, extensive evidence has shown that inflammation develops in the brain during aging and may be the underlying factor for the development of declines in synaptic plasticity in the CNS and neurodegenerative disease. However, the causes and consequences of specific brain inflammatory responses are still not well understood. We have found that amelioration of brain inflammation with various treatments has beneficial actions on several indicators of impaired synaptic plasticity. However, it appears that the more advanced the inflammatory process become, the more difficult it is to reverse its effects. This proposal is aimed at targeting early dysregulating events that activate brain inflammatory pathways to test the hypothesis that learning can be protected during aging by early intervention against inflammation. This will inform us as to critical pathways to target for the development of new interventions to improve cognitive aging.