Over the past decade, evidence has rapidly emerged showing that the borders between the brain and periphery exist to regulate—rather than lock down—what gets in and out of the brain. The long-held view of the brain as an immune-privileged or isolated organ has been revised. We are now in an exciting period of discovery about the mechanisms of brain-periphery crosstalk, the flow of fluids through the brain, and the identification of novel anatomical structures. Remarkably, in just a short period, researchers have translated these basic science discoveries into a deeper understanding of the importance of the brain’s entry and exit routes for Alzheimer’s disease (AD). Impairments in these systems are linked to Alzheimer’s pathologies and to other brain health conditions that involve inflammation.
The goal of the CureAlz Brain Entry & Exit Consortium is to understand how the brain’s built-in systems for regulating what enters and exits it—through the blood and cerebrospinal fluid (CSF)—may contribute to Alzheimer’s pathologies. One of the most well-known of these systems is the blood-brain barrier (BBB). The BBB is a highly selective checkpoint composed of tightly packed cells lining the brain’s blood vessels, supported by other specialized cells (pericytes and astrocytes) that help maintain its stability. Together, these cells communicate with surrounding brain cells to help regulate blood flow, manage the brain’s immune responses, and clear waste.
Beyond the BBB, the brain has another filtering system called the blood-CSF barrier, formed by a structure known as the choroid plexus. The choroid plexus is a small, blood-rich tissue with two key jobs: producing CSF and acting as a filter to ensure that the proper nutrients reach the brain while removing waste. The CSF it produces slowly circulates through the brain, picking up waste products, including amyloid beta, before draining away from the brain. A network of small vessels in the protective membranes surrounding the brain (the meninges) that carry waste fluid into the lymph nodes in the neck has been identified as the brain’s sink. This system, called the meningeal lymphatic system, plays a role in waste clearance and immune surveillance, linking brain health to the rest of the body’s immune system.
Working in concert with these drainage systems is the glymphatic system, the brain’s waste management system. It uses the spaces alongside blood vessels, powered by brain cells called astrocytes, to circulate CSF through brain tissue. As this fluid moves through, it picks up waste products and harmful proteins and carries them away. Notably, this cleaning process is most active during sleep, suggesting a connection between sleep disruption, impaired waste clearance, and neurodegenerative diseases, such as Alzheimer’s.
Together, the BBB, choroid plexus, meningeal lymphatics, and glymphatic network form an integrated system to control what enters the brain, how fluids circulate through it, and how waste is removed. These systems are intricately connected. Dysfunction in any one component can disrupt them all, leading to fluid imbalances, the buildup of harmful proteins, and inflammation in the brain. Studying these systems together, rather than in isolation, is important for a better understanding of how their combined dysfunction contributes to Alzheimer’s.
The Brain Entry & Exit Consortium is well-positioned to advance the field and is already making major strides. The Consortium brings together experienced investigators with a track record of collaboration and with highly complementary cutting-edge expertise across methods, species, cell types, and brain and peripheral systems. Their projects collectively address the broader hypothesis that disruptions in barrier systems allow for waste products (like amyloid beta) to build up in the brain during Alzheimer’s disease, further driving inflammation and degeneration. They expect that finding ways to improve the function of these systems will lead to beneficial treatments for Alzheimer’s patients. The Consortium investigators meet regularly to discuss data and progress with each other and collaborate across projects and labs.
BRAIN ENTRY & EXIT CONSORTIUM: FUNDED RESEARCHERS
Helene Benveniste, M.D., Ph.D., Yale University School of Medicine
Se Hoon Choi, Ph.D., Massachusetts General Hospital
Richard Daneman, Ph.D., University of California, San Diego
Ali Ertürk, Ph.D., Helmholtz Munich, Germany
Ming Guo, Ph.D., Massachusetts Institute of Technology
Fanny Herisson, M.D., Ph.D., Massachusetts General Hospital
Roger D. Kamm, Ph.D., Massachusetts Institute of Technology
*Jonathan Kipnis, Ph.D., Washington University School of Medicine in St. Louis
Maria Lehtinen, Ph.D., Boston Children’s Hospital
Fernanda Marques, Ph.D., Minho University School of Medicine
Maiken Nedergaard, M.D., D.M.Sc., University of Rochester
Daniel S. Reich, M.D., Ph.D., National Institutes of Health
Laura Santambrogio, M.D., Ph.D., Weill Cornell Medicine
Allen Tannenbaum, Ph.D., Stony Brook University
*Chair