In this post, we go into the genetics research behind a highly controversial concept: “leaky brain.” Read on to find out if genetics can play a role in blood-brain barrier integrity.
Can the Blood-Brain Barrier be “Leaky”?
Like the gut barrier, the blood-brain barrier is lined with one layer of cells that separate the blood from the brain. It only allows a few substances like oxygen, hormones, and certain cytokines in, while blocking out others .
“Leaky brain” was coined as a non-medical term for increased blood-brain barrier permeability .
This term is still relatively new and research is sparse. The whole theory is theoretical and it has yet to be verified in proper human studies. Findings are still mostly limited to cell culture or brain tissue studies [2, 1].
That said, limited research has linked a compromised blood-brain barrier with “brain fog” or cognitive dysfunction, chronic fatigue, anxiety/depression, neurodegenerative diseases, and other neurological conditions. There’s not enough evidence to support any of these associations [2, 1].
Genetics and “Leaky Brain”
Remember, the SNPs we go over below have only been found to be associated with increased BBB permeability or “leaky brain.” That does not mean having them will necessarily make you more likely to have BBB permeability problems. More work is needed before we determine whether and how much they may raise a person’s risk of increased BBB permeability.
“Leaky Brain” Genetics – Is there a Link?
There are many potential causes of blood barrier issues. These usually involve a complex interaction between genetics and the environment.
Scientists think that the following genes may have some influence on the blood-brain barrier:
- Matrix metalloproteinases (MMPs)
- Tissue Inhibitors of Metalloproteinases (TIMPs)
- Tight junction proteins
- Genes that control oxidative stress
- Genes that control inflammation and susceptibility to autoimmunity
However, the impact of these genes on the BBB in humans is poorly understood.
There’s no direct study that tested the effects of each gene, SNP, or mutation on the strength of the blood-brain barrier. Thus, scientists can only hypothesize the significance of these SNPs from the gene functions and their association with brain disease/injury outcomes in humans.
For example, limited research suggests that MMP2 gene variants (SNPs) may predict to some extent the possible damage done to the brain by ischemic stroke. This hasn’t been proven in large-enough studies [3, 4].
Tight Junction Proteins
Claudin-5 is a tight junction structural protein. It is important for BBB strength. Variants in this gene have been linked to various diseases.
For instance, it was hypothesized that variants of CLDN5 inherited together with the HLA-DQB1 gene (the celiac disease gene) lead to schizophrenia. This theory remains unverified .
Another study carried out among the Chinese population had a similar hypothesis. They suggested that a SNP of CLDN5, rs10314, may be associated with an increased risk of schizophrenia. Large-scale human data are lacking, though .
Another blood-brain barrier protein, P-glycoprotein, transports necessary chemicals through the BBB and protects it from unwanted molecules because it is selective .
Oxidative Stress Genes
In newborns, NOS3 in the cells that line the blood vessel in the brain can mitigate nerve damage due to a lack of oxygen during birth (hypoxic-ischemic encephalopathy). Some experts consider it a disease of a disrupted blood-brain barrier .
rs1800779 and rs1799983 are not associated with the difference in hypoxic-ischemic encephalopathy.
More research is needed.
Mutations in SOD1 are linked to familial ALS .
In addition, mice that have defective SOD1 function have the same leaky blood-brain barrier, blood-spinal cord barriers, and neurovascular units as ALS patients .
This variant is associated with leukoaraiosis (white matter lesions) after stroke, which may be linked to the worsened leaky brain after stroke .
Genetics, Inflammation & Autoimmune Susceptibility
ApoE4 activates an inflammatory pathway in pericytes that disrupt the tight junctions, while ApoE2 and ApoE3 suppress this pathway .
ApoE4 is also famously linked to Alzheimer’s disease .
Alpha 2-Macroglobulin (A2M)
In addition, it is also linked to an increased risk of complications following tissue plasminogen activator treatment .
This has been suggested to predict the outcome of post-ischemic stroke, but more data are needed .
Learn More in the “Leaky Brain” Four-Part Series
You can read about the introduction to the blood-brain barrier and possible causes of “leaky brain” in Parts 1 and 2.
- Part 1: Introduction to the Blood-Brain Barrier, Causes of Leaky Brain, and Resulting Diseases
- Part 2: Factors and Disease States That Cause Leaky Brain
- Part 3: What Is a “Leaky” Blood-Brain Barrier & Can You Improve it?
- Part 4: Can Genetics Impact a “Leaky” Blood-Brain Barrier?