Common Mechanisms of Blood-Brain Barrier Dysfunction to Underlie Many Forms of Damage to the Brain

Researchers here note a signature of blood-brain barrier dysfunction that is common in many forms of damage and injury to the brain, suggesting it to be more broadly relevant to pathology than suspected. There is already good evidence for dysfunction of the blood-brain barrier to be an early feature of neurodegenerative diseases. The specialized cells of the blood-brain barrier line blood vessels that pass through the central nervous system, managing the passage of molecules and cells. When the barrier fails, unwanted molecules such as fibrogen can enter the brain to cause inflammation - and chronic inflammation in the brain is known to be important in the progression of neurodegeneration.

Whether in the wake of a stroke, seizure, massive neuroinflammation, or a blow to the head, the endothelial cells of the blood-brain barrier (BBB) respond with remarkable similarity, according to a new study. Researchers reported that the endothelial cells that make up the BBB normally express a suite of genes that distinguishes them from the endothelia of other organs. However, BBB cells damaged in various ways lost this specialized signature, changing over to an expression profile more akin to endothelial cells in other parts of the body. The findings suggest that common mechanisms of BBB dysfunction underlie different brain injuries and diseases. "This raises the possibility that successfully preventing (or increasing) endothelial cell gene-expression changes that occur in one disease may lead to a potential therapy for other types of CNS disorders."

Tasked with shielding the precious brain from toxic insults while allowing crucial nutrients to cross, the blood-brain barrier is highly selective. Ergo, the endothelial cells that line the brain's vessels are highly specialized, forming ultra-tight junctions and mobilizing molecular transporters not typically found in vessels supplying other organs. Disruption of the barrier is thought to play a hand in the pathogenesis of multiple injuries and diseases.

How do brain endothelial cells change in the face of injury or disease? The researchers tracked gene-expression changes following four different insults known to disrupt the barrier: seizures, stroke, trauma, and experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. They then tracked the permeability of the barrier at three time points. In the earliest, or "acute" phase of each injury, the researchers found only minimal disruption of the BBB. However, in the so-called "subacute phase," which was one or two days later depending on the model, the leakiness of the BBB reached its peak. About a month later, in the "chronic phase," the barrier had partially or fully regained its integrity.

Each injury induced a bevy of gene-expression changes in brain endothelial cells. They varied substantially among injuries in the acute phase, but shared striking commonalities in the subacute phase, when the barrier was leakiest. By the chronic phase, gene expression had largely returned to normal in the stroke, seizure, and traumatic brain injury models, but remained highly altered in the EAE model. Interestingly, the researchers found that the genetic signature of the healthy BBB endothelium was most downregulated in the acute phase of traumatic brain injury, and the subacute phase of stroke, seizure, and EAE. Conversely, genes expressed predominantly in endothelial cells outside of the brain were turned up in the brain endothelium at these time points. Together, the findings suggest that while brain endothelial cells may initially respond differently to unique insults, they soon converge on a gene-expression profile that resembles those of endothelial cells in other organs of the body. Among other functions, these gene-expression changes likely ramp up interactions between the endothelium and circulating immune cells.

Link: https://www.alzforum.org/news/research-news/scientists-discover-common-distress-signal-blood-brain-barrier

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