An accumulating body of evidence suggests that cerebral ?microvasculature? disease increases with advancing age and is associated with lacunar stroke, leukoaraiosis, and vascular dementia and Alzheimer disease. The increased blood brain barrier (BBB) permeability/leakage was consider as a consequence of ongoing processes like inflammation, atherosclerosis, and lack of vaso-autoregulation or microthrombosis, although that several recent clinical MRI studies indicate that BBB leakage could be a primary reason for the development of vascular/brain parenchymal injury during aging. The specific alterations in brain endothelial barrier components may ultimately lead to vascular hyperpermeability, extravasation of plasma components and inflammatory response in the brain parenchyma. Although significant effort has been made in defining the gene mutations and risk factors involved in microvascular alteration in vascular dementia and Alzheimer disease, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The proposed study is designed to elucidate critical molecular events in maintaining the integrity of the brain endothelial barrier and how these are altered during vascular aging. It will highlight the structural alteration in major regulator of BBB permeability ?Tight junction complex and how interaction between signaling molecules and structural proteins claudins (Claudin1,-5 and -12), affect the organization and stability of brain endothelial tight junctional complex during the process of vascular aging. Specifically, the following objectives will be evaluated: a) the contribution of claudin-1 and claudin-12 to BBB hyperpermeability during aging, b) the effect of claudin-1 and claudin-12 on claudin-5 expression and function during brain endothelial cell ?aging?c) the role of Sirt-1 in modifying claudin-1 and claudin-12 expression in aging. Collectively, these studies will provide new information related to the mechanisms involved in maintaining the brain endothelial barrier that is relevant not only to aging but also to multiple disease states. Hopefully, this will help to elucidate novel therapeutic strategies to restore vascular hyperpermeability.

Public Health Relevance

Normally, the brain is protected from changes in the bloodstream by the blood-brain barrier situated at the brain blood vessels. Defects in that barrier may be important for developing stroke, epilepsy and other CNS diseases like vascular dementia and Alzheimer disease. The process of aging affects the blood-brain barrier causing leakage and subsequent brain tissue damage. The purpose of this study is to highlight the molecular mechanisms underlying vessel hyperpermeability in aging. This may provide a foundation for developing novel therapeutic strategies to lessen the impact of this disease as well as other neurological conditions that affect the blood-brain barrier.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Special Emphasis Panel (ZRG1)
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Wise, Bradley C
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Keep, Richard F; Andjelkovic, Anuska V; Xiang, Jianming et al. (2018) Brain endothelial cell junctions after cerebral hemorrhage: Changes, mechanisms and therapeutic targets. J Cereb Blood Flow Metab 38:1255-1275
Stamatovic, Svetlana M; Martinez-Revollar, Gabriela; Hu, Anna et al. (2018) Decline in Sirtuin-1 expression and activity plays a critical role in blood-brain barrier permeability in aging. Neurobiol Dis :