Abstract
Fibrinogen (Fg)-containing plaques are associated with memory loss during various inflammatory neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, stroke, and traumatic brain injury. However, mechanisms of its action in neurovascular unit are not clear. As Fg is a high molecular weight blood protein and cannot translocate far from the vessel after extravasation, we hypothesized that it may interact with astrocytes first causing their activation. Cultured mouse cortical astrocytes were treated with Fg in the presence or absence of function-blocking anti-mouse intercellular adhesion molecule 1 (ICAM-1) antibody, or with medium alone (control). Expressions of ICAM-1 and tyrosine receptor kinase B (TrkB) as markers of astrocyte activation, and phosphorylation of TrkB (pTrkB) were assessed. Fg dose-dependently increased activation of astrocytes defined by their shape change, retraction of processes, and enhanced expressions of ICAM-1 and TrkB, and increased pTrkB. Blocking of ICAM-1 function ameliorated these Fg effects. Data suggest that Fg interacts with astrocytes causing overexpression of ICAM-1 and TrkB, and TrkB phosphorylation, and thus, astrocyte activation. Since TrkB is known to be involved in neurodegeneration, interaction of Fg with astrocytes and the resultant activation of TrkB can be a possible mechanism involved in memory reduction, which were observed in previous studies and were associated with formation of complexes of Fg deposited in extravascular space with proteins such as Amyloid beta or prion, the proteins involved in development of dementia.