The human brain is regarded as the most sophisticated, complex system in the known universe. It stands to reason that such a precious system, your internal mainframe computer, should be well protected. To this end the brain is encased in the 7mm thick skull, surrounded by protective cerebrospinal fluid and a protective membrane, the meninges, to protect it from external physical injury.
However, internal damage may occur when damaging substances, such as toxins or disease-causing pathogens, gets transported in the blood stream to the brain. To protect the brain from internal damage, it has its own border control, consisting of a very sophisticated and tightly regulated barrier system that regulates which substances are allowed to enter the brain.
This primary protective boundary exists between the blood microcirculation system and the functional tissue in the brain (made up of neurons and glial cells) as an active exchange platform to transport molecules between the blood and the extracellular fluid of the central nervous system and is aptly called the blood-brain barrier. The blood-brain barrier effectively protects brain tissue from circulating pathogens and other potentially toxic substances. As a result, blood-borne infections of the brain are rare, but at the same time difficult to treat, as many medications are unable to cross the blood-brain barrier.
Structure of the blood-brain barrier:
The blood-brain barrier is a complex structure located between the brain tissue and the vascular system and regulated by multiple cell types, consisting of endothelial cells, pericytes, vascular smooth muscle cells, astrocytes, microglia, and neurons. Each cell type contributes to blood-brain barrier function. The main structure responsible for the barrier properties of the blood-brain barrier are tight junctions between the microvascular endothelial cells.
The core anatomical element of the blood-brain barrier is the cerebral blood vessel, formed by endothelial cells. Endothelial cells line the interior of all blood vessels. However, the endothelial cells of the blood capillaries in the blood-brain barrier are wedged extremely close to one another to form tight junctions that restrict the passage of substances from the blood more selectively than endothelial cells of capillaries elsewhere in the body.
The endothelial cells of the blood vessel in the blood-brain barrier are surrounded by other components of the blood-brain barrier that are not really involved in preventing molecules from passing into the brain, but plays a role in how selective the blood-brain barrier is.
Pericyte cells are embedded in the capillary basement membrane and wrap around endothelial cells. They play an important role in blood vessel formation, maintenance of the blood-brain barrier, and control of brain blood flow.
The endothelial cells are surrounded by astrocyte cell projections, called astrocyte feet, which provide biochemical support to the endothelial cells. Astrocytes and their end feet form a second physical and metabolic barrier around pericytes and endothelial cells. Astrocytes are star shaped glial cells that hold nerve cells (neurons) in place and are the most abundant cells in the brain. They form a link between the endothelium and neurons. They communicate with neurons, and, together with pericytes, also transmit neuronal signals to blood capillaries.
How the blood-brain barrier works:
According to the Queensland Brain Institute, the main purpose of the blood-brain barrier is to allow vital nutrients to reach the brain, while protecting the brain against circulating pathogens or toxins that could cause brain infections. It also helps to maintain relatively constant levels of hormones, nutrients, and water in the brain, to prevent fluctuations that could disrupt this “finely tuned” environment.
As a dynamic interface between the peripheral blood circulation and the central nervous system (brain and spinal cord), the blood-brain barrier allows oxygen and nutrients into the central nervous system according to the needs of neural cells, as well as the clearance of cellular metabolites and toxins from the brain to the blood.
The tight gap between endothelial cells allows only small molecules, fat-soluble molecules, and some gasses (such as oxygen and carbon dioxide) to pass freely through the endothelial cells in the capillary wall and into (and out of) brain tissue. Some of the larger molecules that the brain needs, such as glucose, enter the brain by means of transporter proteins, whose function can be compared to opening a special door for specific molecules.
To maintain homeostasis in the central nervous system, the blood-brain barrier is highly selective, as it only allows certain substances to cross from the bloodstream into the brain. It allows the passage of some small molecules by means of passive diffusion, also allowing the active and selective transport of various nutrients, ions, and macromolecules, for example glucose and amino acids, from the blood to the brain. The passage of pathogens, toxins, and entry of peripheral inflammatory mediators, which can impair neurotransmission, are restricted. Even the entry of certain circulating neurotransmitters, such as glutamate, are restricted, as too high levels can be potentially damaging to neurons.
Consequences of a leaky blood-brain barrier:
This highly protective barrier can become permeable under certain circumstances, leading to undesirable substances entering and causing internal damage to the brain.
One such circumstance is bacterial infection, such as meningococcal disease. Bacteria binding to the endothelial wall can cause tight junctions to open slightly and becoming more porous, allowing bacteria and other toxins to infect the brain tissue, and leading to inflammation or worse conditions.
The permeability of the blood-brain barrier increases in almost all diseases of the central nervous system, such as Alzheimer’s disease, Parkinson’s disease, ischemic stroke, epileptic seizures, amyotrophic lateral sclerosis, diabetes mellitus, glaucoma, as well as when brain trauma occurs. In multiple sclerosis, for example, a permeable blood-brain barrier allows white blood cells to infiltrate the brain and affect the signaling function between neurons.
Low-grade systemic inflammation increases permeability of the blood-brain barrier and affects as many as 40% of people in Western countries due to conditions such as insulin resistance, type 2 diabetes, arterial hypertension, obesity, and metabolic syndrome (high blood sugar, high blood pressure, excess body fat, and abnormal cholesterol). Aging and sleep disturbances (affecting the circadian clock and the efficient removal of brain metabolic waste which happens during sleep) can also contribute to permeability of the barrier.
Blood-brain barrier dysfunction can range from mild changes in permeability due to tight junction opening, to chronic barrier breakdown. Changes in transport systems across the barrier can also occur. Infiltration of undesirable plasma components can disturb the homeostasis of the central nervous system and damage the surrounding brain.
Research has shown that the gut and brain are intricately connected and are able to communicate in a bi-directional manner. Quite like the permeability of the blood-brain barrier, the intestinal wall can become permeable. When the intestinal wall gets damaged, either due to certain triggers, inflammation, or oxidative stress, the tight junctions between the epithelial cells that make up the intestinal wall open up and become permeable, which allows substances such as toxins that would otherwise be secreted to travel into the inner layer of the intestinal wall and into the blood stream. As the gut and brain communicate in a bi-directional way, disturbances in the brain from physical or psychological stress can affect gut function. Imbalances in the gut environment can produce behavioral and neuro-chemical changes. Many of the conditions that have a negative impact on the integrity of the blood-brain barrier are also associated with a disrupted gut microbiome composition.
Breakdown of the blood-brain barrier is characterized by several conditions which can result in neuroinflammation, neurodegeneration, and neuronal dysfunction in the brain:
- Increased permeability.
- Reduced tight junction structure.
- Disruption of the basement membrane.
- Impaired transporter function.
- Detachment of the pericytes.
- Swollen end-feet or loss of astrocytes.
- Insufficient clearance function.
It is not clear whether a compromised blood-brain barrier is the cause of disease onset, or a result of neurological disease progression. Disturbance of the blood-brain barrier seems to contribute to or worsen developing diseases.
Exercise affects blood-brain barrier permeability:
Physical inactivity is deemed to be a primary cause of several chronic diseases. Regular exercise is known to have beneficial effects in different systems, such as muscular, metabolic, neural, respiratory, thermoregulatory, and cardiovascular systems. In the cardiovascular system, for example, exercise improves some of the cardiovascular risk factors, such as percentage body fat, insulin resistance, inflammation, and high blood pressure, which are associated with increased stiffening of the arteries.
There is growing evidence that long-term physical activity may reduce blood-brain barrier permeability as, amongst other benefits, it reduces inflammation, improves endothelial function through increased blood flow, and might increase the density of brain capillaries.
Conclusions:
While breakdown of the blood-brain barrier is a common hallmark of all neurogenerative diseases, it remains inconclusive whether blood-brain barrier breakdown is one of the initial events that leads to neuronal cell damage or death, or whether it is a downstream consequence of these diseases.
Researchers today recognize that the blood-brain barrier is not just an anatomical barrier at the blood-brain interface, controlling the exchange of molecules in and out of the central nervous system, but is viewed as an integral part of a complex cellular interplay, whose members interact permanently and regulate each other’s functions.
This complex cellular interplay at the blood-brain barrier is but one small part of the most sophisticated, complex system in the known universe – the human brain.
References:
What is the blood-brain barrier? Published online. Queensland Brain Institute. The University of Queensland. Australia. (www.qbi.uq.edu.au)
Know your brain: Blood-brain barrier. Published online. Neuroscientifically Challenged. (www.neuroscientificallychallenged.com)
Blood-brain barrier. Published online and last edited 22 December 2022. Wikipedia. (www.wikipedia.org)
A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Published 18 November 2020. Fluids and Barriers of the CNS. (Journal). Article number 69 (2020). BioMedCentral. (www.fluidsbarrierscns.biomedcentral.com)
Blood-brain barrier permeability and exercise. Published 24 January 2019. Journal of Neuroinflammation. BioMedCentral. (www.jneuroinflammation.biomedcentral.com)
Blood-brain barrier dynamics to maintain brain homeostasis. Published 7 January 2021. Trends in Neurosciences, Volume 44, Issue 5, P393-405, Mag 01, 2021. A Cell Press Journal. (www.cell.com)
Development, maintenance, and disruption of the blood-brain barrier. Published 5 December 2013. PubMedCentral. National Centre for Biotechnology Information. US National Library for Medicine. National Institutes of Health. USA. (www.ncbi.nlm.nih.gov)
Factors influencing the blood-brain barrier permeability. Published 1 August 2022. Brain Research. Volume 1788. 1 August 2022. Science Direct. (www.sciencedirect.com)
The connection between leaky gut and leaky brain. Mindd Foundation. (www.mindd.org)
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