Aging leads to an increased susceptibility to infiammation, caused by either neuronal degeneration orexternal triggers, such as high-fat diets or toxins. Recent studies have suggested that some neuronalpopulations in the brain may act as neuroprotective entities, providing regulation at the level of microglialactivation. For example, disruption of locus coeruleus (LC) -noradrenergic (NE) innervation activatesmicroglial cells and leads to altered function of both hippocam pal neurons and dopam ine neurons of thesubstantia nigra (SN). Inflammatory pathways are chronically activated in the aged brain, and elevations inpro-inflammatory cytokines cause disruption of the blood-brain barrier (BBB) and lead to microglialactivation. NE protection against inflammation functions by regulating the expression of inflammatory genesin the brain, and NE innervation also affects the integrity of the BBB. Degeneration of LG-NE that occurs innormal aging may therefore cause the observed inflammatory and BBB-related changes reported, butmechanisms for these events have not been examined. We propose to investigate the interaction betweenLG-NE loss with aging, pro-inflammatory cytokines, BBB integrity, and hippocampal-dependent memory loss.Two models are proposed: one that inflicts microglial activation by a High-fat/high cholesterol (HFHC) diet,and one model specific to the brain, using the NE selective toxin DSP-4. We believe that these two modelsexacerbate aging processes and can be utilized to examine specificity of NE-influence upon BBB andneuroinflammation. Reversibility of NE-degeneration induced damage will also be explored using NE-enhancing drugs. Based on our findings, we propose the following central hypothesis: BBB disruptionoccurring with aging is regulated by NE and contributes to age-related neuroinflammation and associatedmemory loss.t
'ons):Age-related memory loss is an increasing public health problem today, due to increased longevity and thebaby boomer generation. Studying basic mechanisms for this problem may lead to translational therapeuticavenues for treatment and intervention.
