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Mechanisms of neurodegeneration by a fibrinogen-containing protein complex during traumatic brain injury

创伤性脑损伤期间含纤维蛋白原的蛋白质复合物引起神经退行性变的机制

基本信息

批准号：
10402868
负责人：
DAVID LOMINADZE
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402868
关键词：
Address Animals Antisense Oligonucleotides Astrocytes Binding Blood Blood Proteins Blood Vessels Brain Caveolae Cognition Complex Data Deposition Disease Endothelial Cells Endothelium Female Fibrinogen Hippocampus (Brain)Immunohistochemistry Impaired cognition Impairment In Vitro Inflammation Inflammatory Intercellular adhesion molecule 1 Link Mediating Membrane Proteins Memory Memory impairment Morbidity - disease rate Mus Nerve Degeneration Neuronal Dysfunction Pathogenicity Pathologic Pathology Pathway interactions Patients Permeability Phosphorylation PrP Process Proteins Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Research Priority Resistance Short-Term Memory Signal Transduction Small Interfering RNA Stains Stimulus Testing Transgenic Organisms Traumatic Brain Injury United States National Institutes of Health Vascular Cognitive Impairment Vascular Diseases Vascular Endothelium Vascular Permeabilities Western Blotting base caveolin 1 cell motility cerebral microvasculature cerebrovascular cerebrovascular pathology controlled cortical impact design fluoro jade in vivo loss of function male mortality neurovascular novel object recognition overexpression protein complex transcytosis

项目摘要

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 HFg mice. Fg-PrPC complex and ROS formations, levels of TrkB, astrocyte activation, and neuronal degeneration assessed by NeuN will be evaluated by immunohistochemistry and Western blot. STM will be assessed by novel object recognition test, Barnes maze and Y-maze tests.

项目总结