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A leaky brain may promote inflammation

New data shows one blood protein may be key

By Austin Perlmutter, MD



  • Damage to the blood-brain barrier is linked to conditions like Alzheimer's and Multiple Sclerosis

  • A recent study suggests that blood getting into the brain may trigger activation of the brain immune cells

  • One of the key proteins in blood linked to brain immune activation is fibrinogen, a protein involved in blood clotting

  • This new research is some of the first data showing that blood proteins are capable of activating brain immune cells in a way that could promote development of brain disease.

One of the most unique and important aspects of our brains is the blood-brain barrier (BBB), a structure made up of multiple types of brain cells that protects the brain from microbes and other potentially harmful elements in our bloodstream. Damage to the BBB is thought to be a contributor to a number of brain health issues ranging from the brain impact of stroke to traumatic brain injury (TBI) to Alzheimer’s disease and Multiple Sclerosis. It’s also believed that the integrity of the BBB may decline as we age. The exact mechanisms by which damage to the blood brain barrier creates brain issues have been challenging to pin down.

Generally speaking, damage to the BBB and subsequently a more “leaky” BBB may lead to a number of brain issues ranging from electrolyte disturbances to swelling and damage to neurons. In addition, it’s believed that disruption in the health of the BBB may promote inflammation in the brain. As one of the principal roles of the BBB is to keep blood from the periphery out of the brain, a major reason why breakdown in the BBB is problematic is the potential for blood components to interact with and alter the health of brain cells. Now new research finds a potential pathway by which blood components might trigger changes in brain immune cells in the context of a damaged BBB.

In a preclinical study published in June 2023 in Nature Immunology, researchers sought to understand whether blood that makes its way into the brain may trigger an immune reaction. They tested this by injecting blood into the brains of mice and then examining effects on brain immune cells called microglia. In addition, the researchers tested the direct effects of blood proteins on microglial cells by exposing microglial cells in culture to the proteins.

After exposing mouse brains to blood, researchers showed that microglial cells taken from the brains had a number of changes in their gene expression, including alterations linked to Alzheimer’s disease and brain degeneration. One blood protein that was of particular significance was fibrinogen, a key for blood clotting. When fibrinogen was removed from the blood injection, the negative changes in microglial cells were largely absent. Further analysis showed that an activated version of fibrinogen called fibrin may activate gene pathways in microglial cells. This suggests that fibrinogen is a key blood protein that may negatively impact the brain’s immune cells.

The results of this study are notable in that they represent some of the first data showing that specific, normally occurring blood proteins are capable of activating brain immune cells in a way that could promote development of brain disease. As the researchers point out, leakiness of the blood brain barrier is sometimes thought to be a result of inflammation, so these results reverse the order of this relationship. While the data presented here are preliminary and the result of pre-clinical study, these types of findings may have particularly important implications for development of conditions like Alzheimer’s and Multiple Sclerosis.

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