Fatty Acid-binding Protein 4 Exacerbates Blood-brain Barrier Disruption Through the JNK/c-Jun/MMP12 Pathway After...

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Elevated circulating fatty acid-binding protein 4 (FABP4) levels are linked to poor prognosis in brain injury patients.
• The precise molecular mechanisms by which FABP4 contributes to blood-brain barrier (BBB) disruption following traumatic brain injury (TBI) are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying FABP4's role in BBB disruption after TBI.
• To evaluate the therapeutic efficacy of the selective FABP4 inhibitor BMS309403 in mitigating TBI pathology.

Main Methods:

• FABP4 expression analysis in TBI mouse models and BV2 cells using Western blot and immunofluorescence.
• Assessment of BBB integrity, neuronal apoptosis, and neurological deficits in Fabp4 knockout mice and wild-type controls.
• Investigation of downstream signaling pathways (JNK/c-Jun/MMP12) and validation using transcriptome sequencing and ChIP-qPCR.

Main Results:

• FABP4 expression was significantly upregulated in TBI models.
• Genetic deletion of FABP4 ameliorated TBI-induced BBB disruption, reduced lesion volume, cerebral edema, neuronal apoptosis, and improved neurological function.
• FABP4 was found to promote tight junction protein degradation and increase BBB permeability via the JNK/c-Jun/MMP12 pathway; BMS309403 treatment preserved BBB integrity and improved outcomes.

Conclusions:

• FABP4 exacerbates BBB disruption post-TBI through the JNK/c-Jun/MMP12 signaling cascade.
• Targeting FABP4 with inhibitors like BMS309403 presents a promising therapeutic strategy for TBI.