The blood-brain barrier is composed of various membranes that separate the central nervous system (CNS) and the peripheral circulatory system. The purpose of this barrier is to allow the passage of nutrients and cell signals from the bloodstream to nerves and supporting cells in the CNS while excluding harmful substances. Genetic predispositions, environmental exposures, and aging may weaken the integrity of this barrier, allowing endotoxins and inflammatory immune cells to infiltrate the brain, contributing to accelerated brain aging and the risk of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
Environmental factors shown to modulate the blood-brain barrier include:
Blood vessels throughout the body are lined with a single layer, or sheet, of endothelial cells, a specialized type of epithelial (i.e., skin-like) cell. The luminal (inner) side of the endothelial sheet interfaces directly with the bloodstream and contains transporters that exchange nutrients and waste. The basal (outer) side of the endothelium at the blood-brain barrier connects mostly to pericytes, which are multipurpose cells that control the dilation and constriction of blood vessels and secrete paracrine and endocrine signals. Astroglia, star-shaped cells with many arms, connect the endothelium and pericytes of the vascular system to neurons in the CNS.
This multicell structure and its many sets of connecting membranes is called a neurovascular unit and serves the purpose of nutrient and waste exchange while providing many points of regulation to prevent neuronal damage. In addition to creating connections between blood vessels and neurons, astrocytes also connect blood vessels to each other, forming a circuit for waste disposal, called the glymphatic system. This system of highly controlled fluid movement is responsible for waste disposal during sleep, injury, and illness because, unlike other organs, the brain has no traditional lymphatic structures. Glymphatic dysfunction disturbs normal pressure in the brain and impairs waste disposal, contributing to neurodegeneration.
"The composition of [fatty acids in the cell membranes] is a determining factor in membrane permeability, with saturated fats increasing rigidity and reducing permeability and unsaturated fats making membranes less compact and more fluid." Click To Tweet
Membranes throughout the body are composed of a phospholipid bilayer. Each phospholipid unit contains a hydrophilic (i.e., water-loving) head and a hydrophobic (i.e., water-averse) tail. These units arrange themselves so that the hydrophobic tails condense in the center of the membrane while the hydrophilic heads face toward the inner and outer membrane surfaces. The most common phospholipids in the body contain an amino acid or carbohydrate as part of the head, connected to glycerol and two fatty acids for the tail. The composition of these fatty acids is a determining factor in membrane permeability, with saturated fats increasing rigidity and reducing permeability and unsaturated fats making membranes less compact and more fluid.
The long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is an example of this, containing 22 carbons and six points of unsaturation where cis-oriented double carbon bonds create kinks in the phospholipid structure. Compared to phospholipids containing saturated fats, which are easily stacked and condensed, phospholipids containing DHA create a very fluid structure. Generally, membranes that are more fluid facilitate the movement of receptors, transporters, and other structures embedded in the membrane, improving cell metabolism.
Membrane fluidity also modulates transcytosis, the process by which molecules move from the bloodstream, through the inside of endothelial cells and then into the surrounding tissue. An example of transcytosis is the movement of iron across the blood-brain barrier via the formation of membrane pouches called caveolae (from the Latin word for "little caves"). The movement of iron in the brain is tightly controlled to maximize enzyme efficiency without causing excessive oxidative damage. Iron is shuttled through the bloodstream by the protein transferrin. When the transferrin-iron complex binds to transferrin receptors on endothelial cells, the physical shape of the receptor changes, initiating a cascade of motion. The receptor and surrounding membrane are pulled into the cell, while scaffolding proteins called caveolin coat the budding membrane and help pinch it closed.
The finished vesicle can be visualized as a sphere made of cellular membrane coated with caveolin on the outside and filled with fluid from the bloodstream. The transferrin receptor complex is located inside the membrane vesicle and is released in a regulated way inside the cell or secreted to surrounding cells needing iron. Transcytotic vesicles such as caveolae facilitate effective sorting of cellular packages, delivering cell signals to the Golgi apparatus, hormones to the endoplasmic reticulum, and cellular debris to lysosomes; however, this system can be hijacked by pathogens such as viruses, which use it to invade cells. Therefore, the benefits of efficient metabolic exchange must be weighed against the risk of infection and injury. Compared to endothelial cells in peripheral organs such as the lungs, which utilize caveolae and other methods of vesicle-mediated transcytosis to a large extent, endothelial cells at the blood-brain barrier severely limit transcytosis.
Transcytotic vesicles often form in lipid rafts, areas of the cellular membrane enriched with saturated fats and cholesterol that serve to stabilize the vesicle structure. Therefore, cells of the blood-brain barrier are enriched with DHA, which has a long, irregular shape that prevents the membrane condensation needed to form caveolae. In order to accumulate DHA, blood-brain barrier endothelia express receptors such as Mfsd2a that transport lipids across the barrier.
Findings from a 2017 study demonstrate that Mfsd2a is needed to suppress caveolae-mediated transcytosis and protect the integrity of the blood-brain barrier. The authors of the report had previously shown that Mfsd2a, a transmembrane protein found exclusively on the endothelial cells of the blood-brain barrier, is the sole means by which phospholipid DHA is delivered to the brain. In a follow-up experiment, using mice that carried a mutation blocking Mfsd2a’s capacity to transport DHA, the investigators assessed barrier function as well as caveolae formation and activity in the animals' brains. Then they compared the lipid composition of brain endothelial cells to lung epithelial cells, which lack Mfsd2a.
Endothelial cells making up the blood-brain barrier had uniquely high levels of DHA. They found that mice that lacked Mfsd2a function had reduced blood-brain barrier integrity and greater caveolae formation and activity than normal mice. In normal mice, they also found that brain endothelial cells had higher lipid concentrations than lung epithelial cells. The most abundant lipid was DHA, which was found in concentrations that were two to five times higher. These findings suggest that Mfsd2a-mediated transport of lipids, particularly DHA, impairs caveolae activity, thereby preserving blood-brain integrity.
More discussion of the role of Mfsd2a, DHA, and the brain in this peer-reviewed article by Dr. Rhonda Patrick:
The intestinal barrier is the largest membrane interface between the body and the outside world. Similar to all membranous barriers, it serves the purpose of exchanging nutrients and waste, but on an exponentially larger scale than most. Also similar to other membranous barriers, the intestinal barrier loses function with age and disease. Increased intestinal permeability, also known as "leaky gut," compromises the health of the whole body by allowing the passage of pathogens and toxins from food and beverages to enter the bloodstream.
Unlike the blood-brain barrier, the intestinal barrier has the added complexity of interfacing with the gut microbiota, the community of microorganisms that inhabits the digestive tract. In order to maintain distance between intestinal cells and pathogens and toxins moving through the digestive tract, the intestinal barrier utilizes physical, chemical, and biological strategies. The intestinal epithelium contains goblet cells that secrete a layer of protective mucus that restricts the growth of bacteria and the movement of toxins. Immune cells located in the intestinal epithelium secrete immune factors into the mucus layer, allowing friendly bacteria to colonize space close to the barrier, crowding out unfamiliar microbes. When this complex filtering system weakens, levels of microbial toxins in the bloodstream rise, a condition known as endotoxemia.
The most common endotoxin found in circulation is lipopolysaccharide (LPS), a lipid and carbohydrate structure shed from the cell walls of Gram-negative bacteria such as Escherichia coli. People with intestinal disorders, such as celiac disease and inflammatory bowel disease, experience chronic barrier disruption and endotoxemia. This phenomenon also occurs in diseases such as obesity and type 2 diabetes, which are characterized by metabolic endotoxemia, a chronic two- to threefold elevation in endotoxins that increases whole-body inflammation and contributes to insulin resistance and weight gain. Many diseases involving the brain also share chronic mild endotoxemia as a feature, including neurodevelopmental disorders such as autism spectrum disorder, neuropsychiatric diseases such as depression, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This wide-ranging list of diseases involving perturbation of the gut-brain axis continues to grow.
Research investigating the role of the gut-brain axis in Alzheimer's disease provides a greater understanding of how endotoxemia affects the blood-brain barrier and greater brain health in the context of aging. The body of available research demonstrates that alterations in the composition of the gut microbiota reduce gut barrier integrity and expose the immune system to pathogen-associated molecular patterns such as LPS. LPS is intercepted by toll-like receptor (TLR)4 on monocytes and endothelial cells, causing systemic inflammation that increases blood-brain barrier permeability and promotes neurodegeneration.
Membrane permeability is required to recruit immune cells and nutrients to areas of damage during an infection or after an injury. Damage-associated molecular patterns (DAMPs) such as high-mobility group protein (HMG)-1, a protein that organizes chromatin and controls DNA transcription, also bind to immune receptors that stimulate inflammation. In the case of DAMP receptor activation, cells of the blood-brain barrier recruit phagocytic (i.e., cell-eating) immune cells such as monocytes to clear cellular debris and stimulate repair. DAMPs such as HMG-1 bind to TLR4 and receptors for advanced glycation end products (RAGE) on cells at the blood-brain barrier to induce an immune response that initially inhibits the deposition of amyloid-beta, a key feature of Alzheimer's disease progression. With chronic activation, the immune system's response accelerates neurodegeneration. Future investigations should expand on this work by discovering therapies that ameliorate DAMP-induced inflammation to treat neurodegenerative disorders.
In obesity, insulin-sensitive tissues such as the liver, adipose tissue, and skeletal muscle are overwhelmed by a chronic intake of excess calories, usually from high-glycemic index foods. To protect themselves from the oxidative stress caused by excess caloric intake, these cells reduce their responsiveness to insulin. As insulin resistance worsens, blood sugar levels become chronically elevated, leading to long-term remodeling of the blood-brain barrier. Changes include the thickening of membranes, a reduction of blood flow, and increased permeability.
One reason for this increased permeability is the production of advanced glycation end products (AGEs), which are lipid and protein structures that have been glycated, meaning chemically bonded to glucose. AGEs directly reduce the expression of the tight-junction proteins in pericytes, permeabilizing the blood-brain barrier and increasing the production of pro-inflammatory cytokines. Obesity further injures the blood-brain barrier by reducing the expression of cytoskeletal proteins necessary for supporting the barrier; transport proteins that facilitate nutrient and waste exchange; and functional proteins such as enzymes, chaperones, and transcription factors. In turn, the blood-brain barrier is less able to transport appetite-suppressing hormones such as leptin into the CNS. Without the proper satiating signals, people tend to overeat, promoting further weight gain.
Mounting evidence suggests that air pollution is harmful to brain health. Pollutants such as ozone, sulfur dioxide, nitrogen oxides, and fine particulate matter emanating from traffic, industry, and wildfires can be inhaled directly into the brain's olfactory bulb or ingested and reach the brain via intestinal- and blood-brain barriers. Once inside the brain, contaminants may trigger immune cells to release cytokines, which drive neuroinflammation. Exposure to airborne pollutants has been associated with neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Preclinical studies suggest that particulate matter air pollution can even interact with and disrupt gut bacteria.
Populations most vulnerable to the damaging effects of air pollution include children and older adults. The structure of the blood-brain barrier shifts across the lifecycle from a developmental state in neonates to a weakened state in old age, potentially allowing contaminants to more readily infiltrate the brain during these stages. Similarly, one in four people carry an APOE4 gene variant, which increases their risk for Alzheimer's disease and may render them more susceptible to air pollution-induced neuroinflammatory damage.
Alarmingly, researchers found early signs of Alzheimer's disease pathology in the brains of children and young adults exposed to high levels of air pollution in Mexico City, an area known for having high levels of air pollution. Autopsy findings revealed elevated levels of amyloid and tau proteins in 202 out of 203 young brains, including an 11-month-old baby.
Preclinical evidence suggests a role for toll-like receptor 4 (TLR4) activation in air-pollution-induced neuroinflammation. Toll-like receptors detect the presence of bacterial components and signal the body to secrete inflammatory cytokines. Airborne particulate matter is sometimes associated with lipopolysaccharides derived from Gram-negative bacteria (PM-LPS) and can activate TLR4 receptors and exacerbate inflammation, particularly in the lungs.
Intestinal permeability - Intestinal permeability is a source of stress for the blood-brain barrier that increases its permeability, injuring neurons and promoting disease.
Toll-like receptors - Toll-like receptors are the principal inducers of innate immunity and participate directly in the loosening of the blood-brain barrier in the setting of endotoxemia.
Aerobic exercise - Exercise reduces age-related changes to the blood-brain barrier that increases leakiness and neurodegeneration.
Polyphenols - Polyphenols and other phytonutrients from plant foods increase neuroprotective metabolites at the blood-brain barrier.
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