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.
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.
|Gardner, Andrew W; Montgomery, Polly S; Zhao, Yan D et al. (2018) Endothelial Cell Inflammation and Antioxidant Capacity are Associated With 6-Minute Walk Performance in Patients With Symptomatic Peripheral Artery Disease. Angiology 69:416-423|
|Ungvari, Zoltan; Yabluchanskiy, Andriy; Tarantini, Stefano et al. (2018) Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults. Geroscience 40:485-496|
|Van Skike, Candice E; Jahrling, Jordan B; Olson, Angela B et al. (2018) Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment. Am J Physiol Heart Circ Physiol 314:H693-H703|
|Ahn, Bumsoo; Pharaoh, Gavin; Premkumar, Pavithra et al. (2018) Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass. Redox Biol 17:47-58|
|Fulop, Gabor A; Kiss, Tamas; Tarantini, Stefano et al. (2018) Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. Geroscience 40:513-521|
|Tarantini, Stefano; Valcarcel-Ares, Noa M; Yabluchanskiy, Andriy et al. (2018) Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell 17:|
|Tarantini, Stefano; Yabluchanskiy, Andriy; Fülöp, Gábor A et al. (2018) Correction to: Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice. Geroscience 40:219|
|Ungvari, Zoltan; Tarantini, Stefano; Donato, Anthony J et al. (2018) Mechanisms of Vascular Aging. Circ Res 123:849-867|
|Tucsek, Zsuzsanna; Noa Valcarcel-Ares, M; Tarantini, Stefano et al. (2017) Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment. Geroscience 39:385-406|
|Tarantini, Stefano; Tran, Cam Ha T; Gordon, Grant R et al. (2017) Impaired neurovascular coupling in aging and Alzheimer's disease: Contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 94:52-58|
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