A case of leaky brain barrier: how missing a piece of chromosome 22 can lead to schizophrenia
Alexis Crockett was the lead author on this study. She is interested in understanding how the rest of the body affects the brain to change behavior. One way the body signals to the brain and changes its function is through activation of the immune system. Her research focuses on how the immune system can become activated, and tries to understand how this inflammation is able to bypass all the barriers that are supposed to protect the brain from this inflammation. She is currently continuing this line of study in her postdoctoral fellowship at the Cleveland Clinic in the laboratory of Dr. Dimitrios Davalos.
or technically,
Disruption of the blood-brain barrier in 22q11.2 deletion syndrome
[See Original Abstract on Pubmed]
Authors of the study: Alexis M Crockett, Sean K Ryan, Adriana Hernandez Vásquez, Caroline Canning, Nickole Kanyuch, Hania Kebir, Guadalupe Ceja, James Gesualdi, Elaine Zackai, Donna McDonald-McGinn, Angela Viaene, Richa Kapoor, Naïl Benallegue, Raquel Gur, Stewart A Anderson, Jorge I Alvarez
Our brains are like car radios -- they tune into different stations for various thoughts and experiences. However, sometimes the station might change without a person touching the radio knob, leading them to hear sounds or voices that are not real in a way that they can't control. Imagine you are on a road trip with your friends, listening to a carefully curated Taylor Swift soundtrack, when all of the sudden, you only hear Kanye West rapping -- while your friends insist that Kanye hasn’t been playing at all! The idea of hearing something that no one else does is super confusing and frightening, especially because sometimes these stations that only you are tuned into could be ominous -- rather than Kanye rapping, you might hear someone that sounds like a scary character from a horror movie. Alternatively, what if you suddenly have zero interest in listening to Taylor Swift despite being known as her biggest fan for years? Such sudden disconnect-from-reality circumstances and/or the lack of interest and emotions are experienced by people with schizophrenia, a chronic mental illness that can seriously interfere with daily life functions. Medicine and therapy can help to manage symptoms of schizophrenia, but there is currently no cure. One reason for the lack of a cure is that we have yet to fully pinpoint the causes of this disorder, making it difficult to inform therapeutic strategies directly targeting those causes.
Scientists have identified many different genetic mutations that are linked to schizophrenia diagnoses. However, these mutations are not found in all individuals with schizophrenia. In addition, people with these mutations do not necessarily develop schizophrenia. A complex combination of genetic, environmental and lifestyle factors contributes to the development of this disorder. Generally, diseases with strong genetic drivers often have more well-defined biological mechanisms, which makes them easier to study. One of the strongest genetic risk factors in schizophrenia is the deletion of a segment of chromosome 22, herein referred to as 22q11.2 deletion, which results in the loss of 40-50 genes. Strikingly, approximately 25% of people bearing 22q11.2 deletion are diagnosed with schizophrenia, putting these people at much higher risk than the general population. Hence, deciphering the commonality among individuals with 22q11.2 deletion might help us better understand the disease mechanism(s). Dr. Alexis Crockett, a former Neuroscience Graduate Group student in the Alvarez lab at University of Pennsylvania, set out to explore how 22q11.2 deletion alters the brain in the way(s) that might cause schizophrenia.
Unlike most organs in the body, the brain is extremely delicate, with limited ability to regenerate if it is damaged. Therefore, to protect the brain, access of substances in the bloodstream to the brain is tightly controlled by a special filter, referred to as the blood-brain barrier. This structure forms a barrier that is critical for keeping various harmful particles such as bacteria, viruses, and environmental toxins from the brain. This brain barrier is made possible by densely packed endothelial cells, which are specialized cells that make up the blood vessels, and the many proteins between them like bricks and mortar, respectively. Therefore, only select substances are allowed to pass through the tiny pores of this barrier, if they are small enough or being transported by specific proteins from the blood-facing side of the cell to the brain-facing side of the same cell. This tight barrier is further reinforced by astrocytes which are a type of brain cell. Given that many of the deleted genes in the 22q11.2 region are proteins that make up this brain barrier, Dr. Crockett and colleagues hypothesized that the brain barrier is leaky in patients with 22q11.2 deletion.
To explore this hypothesis, they employed a mouse model with a similar 22q11.2 deletion as found in humans. Two proteins in the bloodstream, which are known to normally be kept out of the brain, were instead found in the brain tissue of these mice. Furthermore, they observed a marked increase in the amount of ICAM-1, a protein that aids immune cells in sticking to and migrating across the endothelial cell layer. An intact brain barrier normally restricts entry of the immune cells into the brain to avoid uncontrollable inflammation. However, in the brains of mice with 22q11.2 deletion, there was an increased level of inflammatory proteins in astrocytes of the brain. These evidence indicated a breach of brain barrier along with brain inflammation in the mouse model of 22q11.2 deletion.
Although mice are a valuable animal model for biomedical research, there are important differences between mice and humans. For instance, laboratory mice are quite genetically similar to each other, which fails to reflect the genetic complexity of schizophrenic patients. In order to study 22q11.2 deletion in human cells, Dr. Crockett and colleagues obtained cells from patients with this deletion. They then used established methods to change these cells to resemble the endothelial cells that make up the brain’s barrier, allowing them to examine the integrity of the human brain barrier in the dish. Compared to endothelial-like cells derived from healthy individuals, endothelial-like cells derived from patients with 22q11.2 deletion showed an increase in leakiness. Similar to their findings in mice, there was also a higher level of the adhesion protein ICAM-1 in the human endothelial-like cells with 22q11.2 deletion. Indeed, human immune cells readily crossed endothelial-like cell layer, consistent with known effect of high ICAM-1 level on immune cell migration.
Together, the work led by Dr. Crockett demonstrated that in the context of 22q11.2 deletion, the brain barrier is dysfunctional, permitting the entry of prohibited particles, and subsequently triggering inflammation in the brain. Interestingly, impaired function of the brain barrier has been reported in other cases of schizophrenia without clear genetic mutations, suggesting that a leaky brain barrier might be one of the underlying mechanisms contributing to the development of schizophrenia. Dr. Crockett's findings not only help us further understand the complex origins of this devastating disease, but also may lead to better treatment strategies for schizophrenia by targeting the brain’s barrier.
About the brief writer: Phuong Nguyen
Phuong is a PhD Candidate in Dr. Katy Wellen’s lab at Penn. Her research journey started in her undergraduate study at Drexel University when she performed a drug screening on a fruit fly model of Alzheimer’s disease. She then decided to pursue her PhD training in Neuroscience at Penn. She set out to characterize the brain function of a novel mouse model lacking Acly, an important enzyme for lipid synthesis and various metabolic processes. Interestingly, the brain demonstrated a remarkable resilience to the loss of this enzyme, while the skin of those mice was severely damaged that was associated with fat loss and premature death. Her research work revealed a crosstalk among the skin, the fat tissue, and the dietary lipids. She hopes to continue her research in understanding the complex metabolic crosstalk between organs, especially focusing on the brain, and how nutrition impacts those crosstalks.