Blood-Brain Barrier: Everything You Need to Know

For a long time, the blood-brain barrier (BBB) has been imagined as a wall that separates the brain from outside toxins and enemies. But it’s more than that. It’s a jumbled mix of physiological activity that integrates information from the outside with information from the inside so that specific cerebral actions can happen.

In most parts of the body, nutrients squeeze between blood vessel endothelial cells (cells that lie flat and form a kind of pavement along the inner tube of a body cavity) to reach the organs they intend to feed. Not so for the brain — there’s barely enough space even for water to pass through. So how does the brain get the nutrients it needs? Read on to learn all about this incredible filter that keeps us functioning.

Table of contents:

• What is the Blood-Brain Barrier?
• Blood-Brain Barrier’s Function
• Causes of Damage to the BBB
• BBB & DHA
• Taking Care of Your Blood-Brain Barrier

What is the Blood-Brain Barrier?

While the term "barrier" might suggest an impenetrable wall, the blood-brain barrier (BBB) is really more of a protective filter that separates the bloodstream from the brain. This semipermeable barrier, composed of specialized endothelial cells, tightly regulates the passage of substances between the blood and the brain tissue.

It safeguards the delicate brain environment from potentially harmful substances, such as toxins and pathogens, while allowing essential nutrients, oxygen, and other molecules to pass through. Carefully controlling the influx and efflux of these molecules ensures that the brain receives the necessary resources for its complex activities while protecting it from potentially damaging agents.

Blood-Brain Barrier Components

The blood-brain barrier is a complex structure composed of several specialized cell types that work together to form the selective filter we described above. These cells include:

1. Endothelial cells: These form the inner lining of the brain capillaries and are the primary component of the BBB. They are tightly connected to each other by specialized protein complexes called tight junctions, which prevent most molecules from passing between the cells.
2. Pericytes: These cells wrap around the endothelial cells and provide support and structural stability to the BBB. They also play a role in regulating blood flow to the brain and in the maintenance of the tight junctions.
3. Basement membrane: This membrane is a thin layer of extracellular matrix material that surrounds the endothelial cells and pericytes. It provides a structural scaffold for the BBB and also contains proteins that help regulate the passage of molecules across the barrier.
4. Astrocytes: Astrocytes are glial cells that are found throughout the brain and spinal cord. They play a variety of roles in the central nervous system, including supporting neurons, providing nutrients to the brain, and helping to maintain the BBB. Astrocytes are involved in the formation and maintenance of tight junctions between endothelial cells, and they also secrete factors that help to regulate the transport of molecules across the BBB.

Tight Junctions

For a little more context, tight junctions are specialized protein complexes that form seals between adjacent endothelial cells. These seals prevent most molecules from passing between the cells, thus forming the foundation of this barrier between the bloodstream and the brain. Tight junctions are composed of several different proteins, including occludin, claudins, and junctional adhesion molecules (JAMs). These proteins form a continuous network that spans the entire length of the endothelial cell junctions.

Transport Mechanisms

In addition to these cellular components, the BBB also relies on various transport mechanisms to allow the passage of essential molecules. These mechanisms include:

1. Passive diffusion: Small, nonpolar molecules, such as oxygen and carbon dioxide, can passively diffuse across the BBB through the tight junctions.
2. Carrier-mediated transport: Larger molecules, such as glucose and amino acids, are transported across the BBB by specialized transport proteins (discussed in more depth further down). These proteins bind to the molecules and ferry them across the barrier.
3. Receptor-mediated transport: Some molecules, such as certain hormones and growth factors, are transported across the BBB by binding to specific receptors on the surface of endothelial cells. Once bound, the molecule is transported into the endothelial cell and then released into the brain.
4. Adsorption-mediated transport: Small, lipophilic molecules can adhere to the surface of endothelial cells and then diffuse across the membrane. This mechanism is less common than other transport mechanisms and is typically only used for small, lipophilic molecules.

Blood-Brain Barrier’s Function

So to recap, the primary functions of the BBB include:

1. Protecting the brain from harmful substances: The BBB acts as a filter, preventing harmful substances, such as toxins, pathogens, and drugs, from entering the brain and causing damage.
2. Maintaining a stable chemical environment: The BBB regulates the levels of nutrients, hormones, and other essential molecules in the brain, ensuring that the brain has the necessary resources to function properly.
3. Supporting neuronal activity: The BBB plays a role in supporting neuronal activity by providing the brain with essential nutrients and removing waste products.

Because of this, the BBB is not designed to keep everything out, but to escort specific substances in an orderly fashion to the CNS so the brain can acquire the glucose, electrolytes, and amino acids it needs. These materials are guided by protein transporters (mentioned above) that chaperone nutrients to their assigned stations.

An example is the Parkinson’s drug L-dopa, an amino acid that uses another large, neutral amino acid transporter type 1 to reach the brain, where it’s converted to dopamine (in case you’re interested, the type 1 transporter is named 4F2hc/LAT1). This transporter, though, can carry any material disguised by scientists as a legitimate fare, and trick the brain into absorbing it.

Another example is the disguise of glutathione by masking it in a liposome to reach the brain. This method is also used to encase the anti-cancer drug doxorubicin, allowing an enhanced dose of the medication to reach its target. Other transporters of note include a glucose transporter called GLUT1, monocarboxylate transporters called MCT1 and 2, and ion transporters that carry essential elements to the brain. Occasionally, there are errors in which heavy metals may be carried through the BBB, resulting in neurotoxicity.

What Can Cross the Blood-Brain Barrier?

So what actually determines what can cross the barrier by itself, what needs a protein transporter, and what can’t cross at all? The ability of molecules to pass through the blood-brain barrier depends on several factors, including their size, polarity, and charge.

Smaller molecules, nonpolar molecules, and uncharged molecules generally have an easier time crossing the BBB than larger molecules, polar molecules, and charged molecules due to the BBB’s filters. Some common molecules and substances that can cross the blood-brain barrier include:

• Small, lipophilic molecules: These molecules are small enough to pass through the tight junctions between endothelial cells and are also able to dissolve in lipids, which make up the cell membranes. Examples of small, lipophilic molecules include:
• Oxygen: Essential for the brain's metabolism, and is able to cross the BBB by passive diffusion.
• Carbon dioxide: Waste product of cellular metabolism, and is able to cross the BBB by passive diffusion.
• Alcohol: Small, lipophilic molecule that can cross the BBB and reach the brain. This is why alcohol can have psychoactive effects.
• Caffeine: Another small, lipophilic molecule that can cross the BBB and reach the brain. This is why caffeine can have a stimulating effect.
• Molecules that are actively transported across the BBB: These molecules are too large or too hydrophilic to pass through the tight junctions between endothelial cells, so they must be transported across the BBB by specialized carrier proteins. Examples of molecules that are actively transported across the BBB include:
• Glucose: Main source of energy for the brain, and it is transported across the BBB by glucose transporter 1 (GLUT1).
• Amino acids: Building blocks of proteins, and they are transported across the BBB by a variety of amino acid transporters.
• Essential nutrients: Some essential nutrients, such as vitamins and minerals, are transported across the BBB by specialized transporters.
• Drugs: Many drugs are too large or too hydrophilic to pass through the BBB on their own. Some drugs are conjugated to antibodies, which can bind to receptors on the surface of endothelial cells and ferry the drugs across the BBB.

What Can’t Cross?

• Large molecules: Molecules that are too large to pass through the tight junctions between endothelial cells cannot cross the BBB. Examples of large molecules include:
• Proteins: Large molecules that are essential for many biological processes, but they cannot cross the BBB.
• Polysaccharides: Long chains of sugar molecules that are too large to cross the BBB.
• Lipopolysaccharides: Components of the outer membranes of Gram-negative bacteria that are very large molecules. This helps to protect the brain from infection by Gram-negative bacteria.
• Water-soluble molecules: Water-soluble molecules cannot cross the BBB because the cell membranes of endothelial cells are lipid-based, which repels water-soluble molecules. Examples of water-soluble molecules include:
• Inorganic ions: Inorganic ions, such as sodium, potassium, and chloride, are water-soluble and cannot cross the BBB.
• Sugars: This is why glucose, which is a sugar, must be transported across the BBB by a specialized transporter.
• Drugs: Some drugs are water-soluble and cannot cross the BBB. This can make it difficult to treat some neurological disorders with drugs.

Causes of Damage to the BBB

Sometimes there are leaks in the blood-brain barrier. This hyper-permeability may allow some of the harmful substances we’ve discussed to enter the brain and cause inflammation that leads to cognitive problems and even mental illness. Several factors contribute to “leaky brain” syndrome, including systemic inflammation, oxidative stress, infections, head trauma, excess alcohol use, leaky gut, and environmental toxins — to name a few. Household mold fits the last category, but there’s a different sneaky everyday molecule that we’d never think was involved in BBB upset… gluten.

Gluten’s Impact on Blood-Brain Barrier Permeability

We know about gluten’s relationship to celiac disease and gliadin sensitivity, but how did it get wrapped up with the BBB? In 2000, a team of researchers at the University of Maryland Medical School, led by Alessio Fasano, discovered a protein that modulates the permeability of tight junctions. Called zonulin, this is a protein activated by gliadin, a protein component of the gluten common to wheat and the instigator of celiac disease. This is the only recognized physiological modulator of intercellular tight junctions having the potential to allow uncontrolled influx of dietary and microbial antigens, leading to the development and progression of chronic inflammatory disorders. 

No one ever imagined that non-celiac gluten sensitivity would be the driver behind types of psychosis that respond to the removal of gluten from the diet, but here we are. It’s been found that neuro-psychiatric disorders that include schizophrenia, depression, and more are associated with reactions to gluten.

Unfortunately, the complete pathogenesis has not yet been confirmed, but it is established that gluten peptides cross the tight junctions in both the intestine and the BBB. Diagnosis is complex, with many cases unresolved. Later study realized a mechanistic connection between the BBB and the intestinal epithelial barrier, where zonulin values are elevated in both instances of permeability. Especially in multiple sclerosis, zonulin increases levels of inflammatory interleukins and interferons, opening the tight junctions to additional assault.

Conditions Involving Weakened Blood-Brain Barrier Integrity

There are several other conditions and medical concerns that are also associated with abnormally elevated levels of blood-brain barrier permeability, including:

• Brain Infections (meningitis, encephalitis)
• Concussions
• Stroke
• Seizures
• Epilepsy
• Alzheimer's disease
• Parkinson's disease
• Frontotemporal dementia (FTD)
• Amyotrophic lateral sclerosis (ALS)
• Low blood oxygen (hypoxia)
• High blood sugar (hyperglycemia)
• High blood pressure (hypertension)
• High cholesterol (hyperlipidemia)

BBB & DHA

While we want the BBB to block harmful substances, there are times when we want the BBB to be sufficiently permeable to accept substances that help correct physiological upsets. For example, in the case of Alzheimer’s disease — one of the most feared pathologies of our time, particularly among those who carry the APOE-4 allele. It is accepted that APOE-4 carriers respond well to the DHA in fish, but not as well to supplemental DHA. If the difference is that fish carry the fatty acid as a phospholipid, then it makes sense to supply a supplement in the same fashion.

Gut Health & Blood-Brain Barrier Integrity

Proposed by research from the University of California at San Francisco, free DHA is transported across the outer membrane leaflet of the BBB by passive diffusion, and DHA-PC combination crosses the inner leaflet by superfamily domain protein 2A. This leads to the conclusion that APOE-4 carriers lack the capacity to carry the free molecule but the phospholipid combination can cross just fine. Providing phospholipid-transported DHA, then, provides the means to decrease the risk of AD. 

A few years prior to this, French scientists likewise appreciated that DHA is altered in Alzheimer’s and Parkinson’s brains, noting that targeted intake of the fatty acid to the brain could compensate for these deficits. It seems that both pairs of tight junctions have more common attributes than originally thought. While it was initially theorized that mending the gut would also mend the brain, it has now been shown that an intact BBB can be achieved with a gut occupied by a sound microbiome.

In tests using mice free of a normal biome, a permeable and compromised BBB was seen. As soon as a normal microbiome was restored via fecal transplant, so was the BBB. Protection of the BBB might be realized from the most mundane sources. Caffeine blocks disruption of the barrier by preventing extravasation of IgG and fibrinogen caused by a very high-cholesterol diet and by the mere stabilization of the epithelium. By suppressing NF-kB, butyrate and valproic acid (anticonvulsant medication) reduce cerebral artery blockage and subsequent brain edema.

Could Fish Oil be the Solution? Perhaps, But Not All Fish Oil is Equal

Magnesium, a mineral involved in more than three hundred biochemical reactions in the body, supports mitochondria, protects against alcohol damage to the brain, and seriously reduces hyperpermeability of the BBB. Although DHA may be found as a separate supplement, it is most conveniently found in fish oil — but not all forms are equal.

DHA extracted by supercritical carbon dioxide, at very low temperatures, with deliberate fractioning, such as BodyBio’s Fish Oil, is most effective because the integrity of the fatty acids is maintained, and its bioactivity is enhanced. In tests that induced local vertebral ischemia in lab animals, appropriately processed DHA diminishes BBB injury. Where matrix-metalloproteins contribute to the neuroinflammation of MS, n-3 fatty acids are able to decrease their levels and prevent the breakdown of basement membranes.

Taking Care of Your Blood-Brain Barrier

Because the brain has no pain receptors, brain toxicity or injury (called nociception) is not something we have to face. Therefore, for most people, the brain is ignored. As time goes by and some aspects of life dwindle ever so slowly, we need to attend to the brain before it gets too tired to carry on.

To help with this, it’s always prudent to remember to engage your vagus nerve with breath, which you can do by counting inhalation to 5, hold briefly, and exhaling to a count of 10 for a few minutes a day. If we had to choose just one supplement to support the blood-brain barrier, it would be BodyBio PC, a phospholipid complex with four key phospholipids essential for your cell membranes. BodyBio PC also provides the liposomal foundation for the transport of nutrients to the BBB*.