The blood-brain barrier (BBB) is a physiological barrier that keeps many substances that circulate in the rest of the body from getting into the central nervous system, restricting what can cross from circulating blood into the CNS. Nutrient molecules, such as glucose or amino acids, can pass through the BBB, but other molecules cannot. This actually causes problems with drug delivery to the CNS. Pharmaceutical companies are challenged to design drugs that can cross the BBB as well as have an effect on the nervous system.

Like a few other parts of the body, the brain has a privileged blood supply. Very little can pass through by diffusion. Most substances that cross the wall of a blood vessel into the CNS must do so through an active transport process. Because of this, only specific types of molecules can enter the CNS. Glucose—the primary energy source—is allowed, as are amino acids. Water and some other small particles, like gases and ions, can enter. But most everything else cannot, including white blood cells, which are one of the body’s main lines of defense. While this barrier protects the CNS from exposure to toxic or pathogenic substances, it also keeps out the cells that could protect the brain and spinal cord from disease and damage. The BBB also makes it harder for pharmaceuticals to be developed that can affect the nervous system. Aside from finding efficacious substances, the means of delivery is also crucial.

Blood-brain barrier physiological barrier between the circulatory system and the central nervous system that establishes a privileged blood supply, restricting the flow of substances into the CNS.

Glial Cells of the CNS

One cell providing support to neurons of the CNS is the astrocyte, so named because it appears to be star-shaped under the microscope (astro- = "star"). Astrocytes have many processes extending from their main cell body (not axons or dendrites like neurons, just cell extensions). Those processes extend to interact with neurons, blood vessels, or the connective tissue covering the CNS that is called the pia mater (Figure). Generally, they are supporting cells for the neurons in the central nervous system. Some ways in which they support neurons in the central nervous system are by maintaining the concentration of chemicals in the extracellular space, removing excess signaling molecules, reacting to tissue damage, and contributing to the blood-brain barrier (BBB). The blood-brain barrier is a physiological barrier that keeps many substances that circulate in the rest of the body from getting into the central nervous system, restricting what can cross from circulating blood into the CNS. Nutrient molecules, such as glucose or amino acids, can pass through the BBB, but other molecules cannot. This actually causes problems with drug delivery to the CNS. Pharmaceutical companies are challenged to design drugs that can cross the BBB as well as have an effect on the nervous system.

Glial Cells of the CNS

The CNS has astrocytes, oligodendrocytes, microglia, and ependymal cells that support the neurons of the CNS in several ways.

The blood-brain barrier, or BBB, is a dense sheet of cells that surrounds most of the brain’s blood vessels. The BBB’s tiny gaps let vital small molecules, such as oxygen and water, diffuse from the bloodstream into the brain while helping to keep out larger, impermeable foreign substances that don’t belong there.

But in people with certain neurological disorders—such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease—abnormalities in this barrier may block the entry of biomolecules essential to healthy brain activity. The BBB also makes it difficult for needed therapies to reach their target in the brain.

To help look for solutions to these and other problems, researchers can now grow human blood-brain barriers on a chip like the one pictured above. The high-magnification image reveals some of the BBB’s cellular parts. There are endothelial-like cells (magenta), which are similar to those that line the small vessels surrounding the brain. In close association are supportive brain cells known as astrocytes (green), which help to regulate blood flow.

While similar organ chips have been created before, what sets apart this new BBB chip is its use of induced pluripotent stem cell (iPSC) technology combined with advanced chip engineering. The iPSCs, derived in this case from blood samples, make it possible to produce a living model of anyone’s unique BBB on demand.

The researchers, led by Clive Svendsen, Cedars-Sinai, Los Angeles, first use a biochemical recipe to coax a person’s white blood cells to become iPSCs. At this point, the iPSCs are capable of producing any other cell type. But the Svendsen team follows two different recipes to direct those iPSCs to differentiate into endothelial and neural cells needed to model the BBB.

Also making this BBB platform unique is its use of a sophisticated microfluidic chip, produced by Boston-based Emulate, Inc. The chip mimics conditions inside the human body, allowing the blood-brain barrier to function much as it would in a person.

The channels enable researchers to flow cerebral spinal fluid (CSF) through one side and blood through the other to create the fully functional model tissue. The BBB chips also show electrical resistance and permeability just as would be expected in a person. The model BBBs are even able to block the entry of certain drugs!

As described in Cell Stem Cell, the researchers have already created BBB chips using iPSCs from a person with Huntington’s disease and another from an individual with a rare congenital disorder called Allan-Herndon-Dudley syndrome, an inherited disorder of brain development.

In the near term, his team has plans to model ALS and Parkinson’s disease on the BBB chips. Because these chips hold the promise of modeling the human BBB more precisely than animal models, they may accelerate studies of potentially promising new drugs. Svendsen suggests that individuals with neurological conditions might one day have their own BBB chips made on demand to help in selecting the best-available therapeutic options for them. Now that’s a future we’d all like to see.

Cognitive impairment is when a person has problems remembering, learning, concentrating, or making decisions that affect everyday life. Millions of people in the U.S. show some sort of cognitive impairment. People with cognitive impairment are at higher risk for developing dementia, which is the loss of cognitive functioning. Alzheimer's disease is the most common dementia diagnosis.

Researchers have been looking for ways to test for early signs of cognitive impairment and dementia. Early detection could open the door to strategies that prevent disease progression. Potential biomarkers include changes in the size and function of the brain and its parts, as well as levels of certain proteins seen on brain scans, in cerebrospinal fluid, and in blood. People with Alzheimer’s disease, for example, have abnormally high levels of plaques made up of beta-amyloid and tangles made of tau proteins.

To look for earlier biomarkers of cognitive decline, a team led by Dr. Berislav V. Zlokovic at the University of Southern California, Los Angeles, examined two markers involved in the breakdown of the blood-brain barrier. This barrier controls the movement of cells and molecules between the blood and the fluid that surrounds the brain’s nerve cells. Past studies have found that abnormalities in the small blood vessels (capillaries) of the brain often contribute to dementia.

The team enrolled more than 160 people with and without cognitive impairment. They measured levels of the soluble form of a protein called platelet-derived growth factor receptor beta (PDGFRβ). PDGFRβ is found in the capillaries that maintain the blood-brain barrier’s integrity. Levels of the soluble form rise in cerebrospinal fluid when the blood-brain barrier is compromised. The team also tracked the integrity of the blood-brain barrier in 73 participants using an MRI-based technique they’d previously developed. The study was supported in part by NIH’s National Institute on Aging (NIA) and National Institute of Neurological Disorders and Stroke (NINDS). Results were published online on January 14, 2018, in Nature Medicine.

The researchers found that, compared with those without cognitive impairment, those with cognitive impairment had higher levels of soluble PDGFRβ and a greater breakdown in the blood-brain barrier of certain brain regions. Notably, both these measures were independent of beta-amyloid and tau protein levels. The findings suggest these measurements could pave the way for an early diagnostic test for cognitive impairment from Alzheimer’s disease as well as other causes.

“This is a solid step towards an accurate and reliable test that could be an earliest sign of critical brain damage in some people with Alzheimer’s disease and related dementias” says Dr. Roderick Corriveau, a program director at NINDS.

“Because of our aging population and growing public health concerns, efforts to find a reliable and accurate predictor of cognitive impairment and dementia are very important to researchers and the public,” explains Dr. Suzana Petanceska, a program director at NIA. “These early results are showing one possible, promising way to quantify risk.”

The researchers are planning to further validate these results by conducting a second trial with more participants.

The brain is walled off from the rest of the body by the blood-brain barrier. This tightly packed mix of cells sits between the blood vessels that lead to the brain and the brain tissue itself. The blood-brain barrier helps protect the brain from threats like infection. But it can also stop helpful medications from getting to the brain when needed.

Researchers know that the blood-brain barrier isn’t perfect. For example, cancer cells can sometimes get past it and establish metastatic tumors (ones from other locations) in the brain. If scientists could better understand how cancer cells accomplish this crossing, they might be able to develop methods to prevent it.

Many cells, including cancer cells, release tiny sacs called extracellular vesicles (EVs). EVs can affect other cells by transferring proteins and genetic material into them. EVs from tumors, for example, can enter the circulation and alter distant organs to make them more susceptible to metastatic cancer. Because of their ability to alter cells, EVs are being studied as potential therapeutics for cancer and other diseases.

A research team led by Drs. Marsha Moses and Golnaz Morad from Boston Children’s Hospital and Harvard Medical School investigated whether EVs can cross the blood-brain barrier and play a role in brain metastases. The research was funded in part by NIH’s National Cancer Institute (NCI). Results were published on September 3, 2019, in ACS Nano.

The team first injected mice with EVs released from breast cancer cells known to form tumors in the brain. Mice injected with EVs from these cells developed more and larger brain metastases than mice that received EVs from breast cancer cells that hadn’t turned metastatic. Fluorescent tagging of the EVs showed that they crossed the blood-brain barrier.

The researchers next used their laboratory models of the blood-brain barrier to find out how the EVs crossed into the brain. They found that EVs were able to cross the cells of the blood-brain barrier through a process called transcytosis. They were first engulfed with other materials, then moved through the cell, and finally fused with the cell membrane on the other side to be released. In this way, their contents could pass through the blood-brain barrier to the brain.

Using fluorescent imaging of live zebrafish embryos, the researchers were able to watch EVs travel through cells and fuse with cell membranes to be released on the other side.

The team also showed that EVs from metastatic cancer cells altered blood-brain barrier cells to disrupt their ability to break down vesicles. This would allow more EVs to make their way safely across the barrier cells and into the brain. Once inside, the EVs help make the region more hospitable to metastatic cancer cells.

“EVs can manipulate endothelial cells to facilitate their own transport across the blood-brain barrier,” Morad says. “They hijack the pathways involved in the uptake and sorting of molecules.”

The team is now testing whether EVs could be engineered to deliver anticancer drugs across the blood-brain barrier.

—by Sharon Reynolds