Title : Vascular effects during neuroinflammation
Abstract:
Many neuroinflammatory diseases are accompanied by neurodegeneration and memory deficits. In a substantial number of these diseases, deleterious causes originating in vasculature play a significant role in the development and/or progression of morbidity. Traumatic brain injury (TBI) can be considered an example of such a disease. Inflammation that is associated with TBI, results in increased blood content of fibrinogen (Fg), called hyperfibrinogenemia (HFg). During mild-to-moderate TBI, despite no noticeable microvascular ruptures about seven days after injury insult, Fg extravasation was still detectable 14 days after injury. This vascular effect of Fg extravasation resulted in its deposition in the extravascular space in the vicinity of astrocytes and neurons. Similar to our finding of a direct association of Fg with astrocytes and neurons, we discovered that the resultant activation of astrocytes, in conjunction with its direct interaction with neurons resulted in neurodegeneration and a reduction of short-term memory. In this study, we will present data indicating mechanisms involved in the interaction of Fg with astrocytes and neurons, we will show the role of Fg in the generation of reactive oxygen species which contributes to neurodegeneration, and we will document the specific role of Fg in the reduction of short-term memory. Overall, we will show that the HFg that accompanies neuroinflammation leads to increased cerebrovascular permeability via caveolar transcytosis principally, enhances deposition of Fg in extravascular space, and results in neurodegeneration. All these effects directly indicate a significant role of vascular-cognitive impairment during neuroinflammatory diseases such as TBI, Alzheimer’s disease, and others that are accompanied by HFg.
