Fibrinogen-cellular prion protein complex formation on astrocytes

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Traumatic brain injury (TBI) is a common cause of neurological disorders, particularly short-term memory (STM) reduction.
• Increased blood fibrinogen (Fg) during TBI-induced inflammation enhances vascular protein extravasation and deposition at vasculo-astrocyte interfaces.
• Cellular prion protein (PrP^C) deposition also increases in these interfaces, but its association with Fg remains unconfirmed.

Purpose of the Study:

• To investigate the potential association between fibrinogen (Fg) and cellular prion protein (PrP^C) on astrocytes.
• To determine if Fg binding to PrP^C on astrocytes leads to astrocyte activation.
• To elucidate the molecular mechanisms underlying Fg-induced astrocyte activation and its potential role in TBI-related memory deficits.

Main Methods:

• Primary mouse brain astrocytes were cultured and treated with varying concentrations of Fg, with or without function-blocking antibodies against PrP^C or IgG controls.
• Western blot analysis was used to assess protein expression levels in cell lysates.
• Coimmunoprecipitation assays were performed to confirm the association between Fg and PrP^C.
• Immunohistochemistry was employed to evaluate astrocyte activation and PrP^C expression.

Main Results:

• Fg dose-dependently activated astrocytes, increasing the expression of PrP^C, tyrosine receptor kinase B (TrkB), and the PrP gene.
• Blocking PrP^C function significantly reduced Fg-induced astrocyte activation and TrkB overexpression.
• Coimmunoprecipitation confirmed a direct association between Fg and PrP^C.
• Fg/PrP^C interaction led to nitric oxide (NO) production and reactive oxygen species (ROS) generation.

Conclusions:

• Fibrinogen (Fg) directly associates with cellular prion protein (PrP^C) on the surface of cultured mouse brain astrocytes.
• Fg binding to PrP^C induces astrocyte activation, upregulates PrP^C and TrkB expression, and promotes NO and ROS production.
• The Fg/PrP^C interaction represents a novel mechanism potentially triggering the TrkB-NO-ROS axis, contributing to astrocyte-mediated neurodegeneration and short-term memory reduction following TBI.