Project Summary This application addresses problems related to vascular cognition impairment (VCI). Particularly it aims to define mechanisms of vasculo-astrocyte functional connectivity that results in cognitive decline after inflammatory pathologies, e.g. traumatic brain injury (TBI). It is known that increased vascular permeability is involved in pathological alterations in neurovascular network such as accumulation of fibrinogen (Fg) and cellular prion protein (PrPC) leading to neuronal dysfunction and degeneration. However, critical factors that initiate these effects are not known. Our preliminary data indicated that TBI-induced an increase in blood level of Fg, called hyperfibrinogenemia (HFg), and enhanced cerebrovascular permeability to proteins mainly via caveolar transcytosis. This effect caused a greater deposition of Fg and increased formation of Fg and PrPC complex in vasculo-astrocyte interface, resulting in vasculo-astrocyte physical uncoupling and astrocyte activation leading to neuronal degeneration via overexpression of neurotrophic tyrosine receptor kinase B (TrkB) and formation of reactive oxygen species (ROS). These effects were associated with neuronal degeneration and reduction in short-term memory (STM) in mice after TBI. Importantly, treatment of mice with siRNA against caveolae membrane protein caveolin-1 (Cav-1) ameliorated TBI-induced memory reduction. Based on these data, we propose a novel hypothesis that TBI-mediated inflammation increases the blood level of Fg, which via binding to endothelial ICAM-1 activates caveolar protein transcytosis resulting in enhanced Fg deposition and formation of Fg-PrPC complex, which cause astrocyte activation, vasculo-astrocyte uncoupling and subsequent neuronal degeneration (via TrkB-ROS pathway) resulting in STM reduction. This compelling hypothesis provides the crucial link between vascular dysfunction and neuronal degeneration leading to cognition impairment during various cerebrovascular pathologies. The present study should reveal the fundamental, previously unknown mechanism for vasculo-astrocyte uncoupling (altered functional and physical connectivity) leading to neuronal degeneration and memory reduction after TBI. The hypothesis will be tested with three specific aims: (1) To define whether the HFg-mediated caveolar protein transcytosis enhances Fg deposition and Fg-PrPC complex formation in brain extravascular space during TBI. (2) To define whether the Fg-PrPC complex formation in vasculo-astrocyte interface causes vasculo-astrocyte uncoupling and neuronal degeneration leading to reduction in STM during TBI. (3) To define if diminishing caveolae formation in vascular endothelium and Fg-PrPC complex formation can ameliorate neuronal degeneration and STM reduction during TBI. Specific mechanisms of TBI-induced vasculo-astrocyte uncoupling and memory impairment, i.e. VCI, will be studied using cultured endothelial cells and astrocytes, and C57BL/6J wild type and transgenic ...