Aging leads to an increased susceptibility to infiammation, caused by either neuronal degeneration or external triggers, such as high-fat diets or toxins. Recent studies have suggested that some neuronal populations in the brain may act as neuroprotective entities, providing regulation at the level of microglial activation. For example, disruption of locus coeruleus (LC) -noradrenergic (NE) innervation activates microglial cells and leads to altered function of both hippocam pal neurons and dopam ine neurons of the substantia nigra (SN). Inflammatory pathways are chronically activated in the aged brain, and elevations in pro-inflammatory cytokines cause disruption of the blood-brain barrier (BBB) and lead to microglial activation. NE protection against inflammation functions by regulating the expression of inflammatory genes in the brain, and NE innervation also affects the integrity of the BBB. Degeneration of LG-NE that occurs in normal aging may therefore cause the observed inflammatory and BBB-related changes reported, but mechanisms for these events have not been examined. We propose to investigate the interaction between LG-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 models exacerbate aging processes and can be utilized to examine specificity of NE-influence upon BBB and neuroinflammation. 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 disruption occurring with aging is regulated by NE and contributes to age-related neuroinflammation and associated memory loss. t

Public Health Relevance

'ons): Age-related memory loss is an increasing public health problem today, due to increased longevity and the baby boomer generation. Studying basic mechanisms for this problem may lead to translational therapeutic avenues for treatment and intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG044920-02
Application #
8536721
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6 (J3))
Program Officer
Wise, Bradley C
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$264,460
Indirect Cost
$85,165
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425