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.

R01AG047879

2014-08-15

2019-12-31