An accumulating body of evidence suggests that cerebral small vessel disease (CSVD) increases with advancing age and is associated with lacunar stroke, leukoaraiosis, and vascular dementia and Alzheimer disease. CSVD poses one of the major challenges in the aging population, due to high morbidity, related to recurrent ischemic stroke and cognitive disturbance. Recognized as hereditary or idiopathic cases, CSVD is histologically characterized by segmental arteriolar disorganization, perivascular lesions, focal inflammation, and/or microartheroma appearance. One of the common sporadic form of CSVD is Cerebral amyloid angiopathy (CAA) predominantly present in the cerebral cortex, leptomeninges, and gray?white matter junction and characterized by the progressive deposition of amyloid ? peptide (A?) within walls of cerebral arteries, arterioles and capillaries and causing of micro-intracerebral hemorrhage, ischemic and hemorrhagic stroke, and cognitive dysfunction in elderly patients. The pathological substrate for progressive CAA is indicated to be blood brain barrier dysfunction, which is manifest as 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 CAA the intra- and intercellular pathogenic mechanisms responsible for vascular injury are still largely unknown. The proposed study is designed to elucidate critical molecular events in endothelial dysfunction associated CAA. It will highlight how gap junction protein Connexin-43 and its isoform Cx43-20, highly expressed at brain endothelial cells in presence of A?, lead to brain endothelial barrier remodeling and facilitating the vascular injury in CAA vasculopathy. Specifically, the following objectives will be evaluated: a) the role of Cx43 and Cx43-20 in brain endothelial barrier dysfunction and microhemorragy in CAA vasculopathy, b) how Cx43-20 cause the brain barrier dysfunction in CAA vasculopathy, c) the effect of amyloid beta on Cx43-20 expression and function in CAA vasculopathy d) how the targeting CX43-20 may improve vascular stability and prevent CAA induced micro- and macrohemorrage. Collectively, these studies will provide new information related to the mechanisms involved in maintaining the brain endothelial barrier that is relevant not only to CAA but also to multiple disease states. Hopefully, this will help to elucidate novel therapeutic strategies to restore vascular hyperpermeability.
LAY DESCRIPTION Normally, the brain is protected from changes in the bloodstream by the blood-brain barrier situated at the brain blood vessels. One disease that affects the blood-brain barrier during aging is cerebral small vessels disease (CSVD) and its one most common form, cerebral amyloid angiopathy (CAA). The purpose of this study is to highlight the molecular mechanisms underlying vessel injury in this condition. 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.
