Age-related cognitive decline is a fundamental concern within the aging population and is the primary factor that leads to loss of independence. Although the specific mechanisms for age-related cognitive decline are not yet known, there is increasing evidence that age-related inflammatory changes play a crucial role. We and others have provided compelling initial evidence that age-related changes within the cerebrovasculature have a critical role in development of neuroinflammation. Our objective in this proposal is to determine the etiology of age- related pro-inflammatory changes within the cerebrovasculature. Nrf2, a master regulator of both endogenous cytoprotective and anti-inflammatory pathways, the central hypothesis of this application is that age-related endothelial Nrf2 dysfunction promotes cerebromicovascular inflammation and BBB disruption, which have a critical, direct role in chronic low-grade neuroinflammation and the etiology of age-related cognitive decline. We propose that Nrf2 can be manipulated pharmacologically, thus presenting a strong candidate target to pre- vent/reverse cerebromicrovascular impairment and vascular cognitive impairment in the elderly. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the contribution of endothelial Nrf2 dysfunction to chronic low-grade cerebromicro-vascular inflammation in aged mice. Our hypothesis is that Nrf2 dysfunction leads to a pro-inflammatory shift in cytokine expression profile of endothelial cells in the cerebromicrovasculature of aged mice. 2) Determine the contribution of endothelial Nrf2 dysfunction to BBB disruption and perivascular microglia activation in aging. Our hypothesis is that age-related Nrf2 dysfunction promotes BBB disruption resulting in leakage of serum-derived factors to the brain parenchyma, which in turn indirectly exacerbates neuroinflammation by activating perivascular microglia. Increased neuroinflammation is expected to impact neuronal function. 3) Determine the extent to which Nrf2 dysfunction impacts initiation of senescence programs in cerebromicrovascular endothelial cells. We postulate, on the basis of preliminary data, that age-related Nrf2 dysfunction exacerbates oxidative stress, impairs DNA repair path- ways, and thereby increases DNA damage, triggering the execution of senescence program(s) in cerebro- microvascular endothelial cells. We predict that senescent endothelial cells exert pro-inflammatory, pro- oxidative effects on neighboring endothelial cells in a paracrine manner. Together, the proposed studies will identify a fundamental mechanism governing age-related exacerbation of cerebral microvascular inflammation eventually leading to neuronal circuit injury and cognitive impairment.

Public Health Relevance

The proposed research is relevant to public health because vascular cognitive impairment in elderly persons clearly diminishes quality of life, is a major factor in loss of independence, and imparts a costly burden to society. The discovery of the microvascular mechanisms responsible for aging-induced neuroinflammation in the elderly is ultimately expected to increase understanding of the pathogenesis of vascular cognitive impairment and will lead to the development of novel therapeutic interventions for the prevention/treatment of vascular dementia. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of disability in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG047879-01
Application #
8748331
Study Section
Special Emphasis Panel (ZRG1-CB-G (55))
Program Officer
Mackiewicz, Miroslaw
Project Start
2014-08-15
Project End
2019-04-30
Budget Start
2014-08-15
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$303,400
Indirect Cost
$98,400
Name
University of Oklahoma Health Sciences Center
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
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