Our genes control everything from our physical appearance and blood type to our chances of developing certain diseases. But can our genes also dictate how our body heals itself?
ApoE, a protein that controls the transport of fats in the body, also alters inflammatory responses in the brain. In a new study published in the journal Molecular Neurodegeneration, scientists at Georgetown Medical Center set out to determine the role that different variants of the APOE gene play in repairing blood vessels of the brain after an injury.
Approximately 65 million people worldwide suffer a traumatic brain injury (TBI) every year. In the U.S., 5% of affected individuals die and over 40% suffer long-term disability.
Mechanical force from a trauma (e.g., motor vehicle accident, fall, sports injury, blast injury) can bruise the brain and damage the blood-brain barrier.
What is the blood-brain barrier?
Your body puts a lot of effort and resources into protecting your brain. The blood-brain barrier stands guard between your brain and stuff swirling around in your blood. It is a selective barrier that allows nutrients to reach the brain but keeps harmful substances such as toxins and bacteria out. It also prevents molecules that are too large, highly charged, or those with low fat solubility (such as most drugs and proteins) from entering the brain.
The blood-brain barrier is composed of capillaries that are less “leaky” than those that perfuse most of your other organs. This is thanks to tight junctions found between the cells that make up the capillary walls. Tight junctions act like zippers binding the membranes of adjacent cells tightly together, limiting the exchange of substances across the capillary wall.
How does TBI affect the blood-brain barrier?
Traumatic brain injury can rupture the tiny capillaries in the brain and damage the blood-brain barrier. A damaged blood-brain barrier allows larger blood-borne proteins and peripheral immune cells to have unrestricted access to the brain, causing inflammation.
Blood-brain barrier breakdown often controls outcomes of a traumatic injury, controlling how long TBI symptoms last and how long the recovery process takes.
What have genes got to do with it?
Apolipoprotein E (ApoE) is a protein that regulates cholesterol and lipid metabolism in the body. Human ApoE comes in 3 flavors: ApoE2, ApoE3, and ApoE4. Although the three isoforms differ only slightly from each other in structure, they display different properties.
ApoE3 is the most commonly expressed isoform of Apolipoprotein E. ApoE4 increases the genetic risk of Alzheimer’s disease and ApoE2 confers protection from it.
Studies report that suffering a TBI may also increase one’s chances of developing Alzheimer’s disease, especially for individuals with the APOE4 gene variant. Further, blood-brain barrier dysfunction is a common underlying mechanism of both TBI and Alzheimer’s disease. Therefore, authors of a recent study in Molecular Neurodegeneration were interested in understanding how genetic variants of APOE affect blood-brain barrier repair after TBI.
How was the study designed?
As they often do, scientists turned to the workhorse of biomedical research – mice – to study traumatic brain injury and genetic recovery factors. To mimic TBI in male mice, a hole was drilled into the skull and the brain cortex was injured using a device that produces a controlled, focal injury. The researchers then investigated how this injury affected blood-brain barrier (BBB) integrity and repair.
Three kinds of mice were used for these experiments. “Wild type” mice were not genetically altered in any way and expressed the normal mouse APOE protein. However, the structure and expression of mouse APOE is slightly different from human APOE. Therefore, some mice were genetically modified to express the human APOE3 and APOE4 gene variants. Scientists then studied how these different APOE proteins affected blood-brain barrier properties following traumatic brain injury.
What were the main findings?
The researchers found that the leakiness of the blood-brain barrier increased following brain injury in wild-type as well as human APOE3 and APOE4-expressing mice. A dye that under normal conditions is not able to cross an intact blood-brain barrier was injected into the bloodstream of mice. Increased penetration of this dye into the brain indicates a damaged blood0brain barrier. There were also fewer tight junctions between the cells lining the capillary walls after TBI.
In wild-type and APOE3-expressing mice, the blood-brain barrier spontaneously repaired itself over the course of 7 to 10 days following injury. However, APOE4-expressing mice continued to have higher dye penetration into the brain and fewer pericytes and tight junction proteins even 10 days following the brain injury. What does this all mean? The repair of the blood-brain barrier was significantly delayed in mice expressing the APOE4 gene variant, compared to wild-type mice or mice expressing the APOE3 variant.
What does that mean for TBI patients?
Several studies show that the APOE4 genotype is associated with poor outcomes in TBI patients. The APOE4 gene interacts synergistically with TBI to increase the risk of Alzheimer’s disease up to 10-fold. In other words, individuals expressing the ApoE4 protein who experience traumatic brain injury also increase their risk of Alzheimer’s disease. What causes the synergism is not entirely clear. Perhaps this study pointing to a link between APOE4 expression and spontaneous blood-brain barrier repair after TBI may begin to provide some answers.
As we usher in an era of precision medicine, understanding the mechanisms that result in poor outcomes for particular patients based on their genes as well as environmental and lifestyle factors will enable the development of treatments that specifically target the underlying problem to help these genetically vulnerable populations.
