Alon Friedman: Blood-brain barrier dysfunction in neurological disorders: Time for translation

Dalhousie University and Ben-Gurion University of the Negev

Advancements in acute-phase medical interventions for brain insults (e.g. ischemic or traumatic) have significantly enhanced overall survival rates. However, patients commonly contend with persistent, unaddressed long-term complications. I will review our decade of studies on mechanisms linking brain insults to these enduring issues, with a specific focus on the compromised blood-brain barrier (BBB). Ischemic or traumatic insults prompt an immediate reduction in oxygen and metabolite supply to affected brain regions, accompanied by glutamate release, resulting in spreading depolarization (SD)—a prevalent immediate neuronal response to injury. The polarization of cellular and mitochondrial membranes, particularly in vascular-related cells, induces an increase in BBB permeability, facilitating the leakage of serum albumin into the brain neuropil. Subsequently, albumin triggers the transformation of astrocytes into an inflammatory senescence-associated secretory phenotype through TGFβ signaling. This transformation diminishes the capacity of astrocytes to maintain a stable brain's extracellular environment, thereby fostering excitatory synaptogenesis, pathological plasticity, and a predisposition to seizures. Remarkably, a comparable sequence of events has been observed in aging and neurodegeneration, suggesting that brain insults may expedite the aging process. Promisingly, pre-clinical and clinical studies investigating shared pathways underlying neural dysfunction post-insult and during aging offer potential avenues for novel diagnostic and therapeutic approaches.

 

Guests are welcome!

 

Organized by

Jens Dreier / Margret Franke