Despite evidence demonstrating that impairments in the clearance of toxic waste in the brain contribute to late-onset Alzheimer’s disease, the science of lymphatic system dysfunction and the systems regulating entry and exit through the blood-brain barrier has been largely overlooked in Alzheimer’s disease — until now. The Maxine and Richard Berg Brain Entry & Exit Consortium bring together an international team of scientists to consider the following question: how do different barriers within the brain communicate?

The recent discovery of lymphatic vessels in the brain has raised important questions.  How are fluids, such as cerebrospinal fluid and various molecules, exchanged between different parts of the brain? How are toxic waste and other byproducts cleared from the brain? It took more than 200 years and the application of cutting-edge imaging techniques for the observation in the 18^th century by Paoli Mascagni to be confirmed: the membranes that line the skull and enclose the brain and spinal cord contain lymphatic vessels that drain fluids from the brain.

The brain is comprised of multiple barriers including the blood-brain barrier, the blood-choroid plexus barrier, meningeal lymphatics, and the blood-meningeal barrier. The meningeal lymphatic vessels carry waste from the cerebrospinal fluids (CSF) to the lymph nodes and facilitate the removal of byproducts from the brain. While it is known that the brain recirculates the CSF, the details for how this process might change during aging, and the role of CSF and recirculation in neurodegeneration, requires more investigation. The CSF also regulates intracranial pressure, removal of waste such as amyloid-beta, and neuroinflammation. A decrease in CSF production and clearance is thought to contribute to the dysregulation in the brain that arises with aging and neurodegenerative diseases.

With grants from Cure Alzheimer’s Fund, these investigators are embarking on research that will determine how dysfunction in one of the brain barriers might impact others. And, since many drugs and antibodies do not make it to the brain because they are blocked by the blood-brain barrier, this research is critical for designing better systems of drug delivery.

The members of the Maxine and Richard Berg Brain Entry & Exit Consortium includes:

JONATHAN KIPNIS, PH.D., WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS, CHAIR OF THE CONSORTIUM

• Explore interactions between meningeal lymphatics and other barriers in the brain.
• Characterize routes for blood-derived antibodies to reach the brain.

FERNANDA MARQUES, PH.D., UNIVERSITY OF MINHO SCHOOL OF MEDICINE

• Characterize the blood-choroid plexus barrier in young, old, and Alzheimer’s disease model mice.
• Examine changes in this barrier that occur when there is a dysfunctional BBB or dysfunctional meningeal lymphatic vessels.

RICHARD DANEMAN, PH.D., UNIVERSITY OF CALIFORNIA, SAN DIEGO

• Explore how the blood-brain barrier changes during Alzheimer’s disease.
• Determine how changes in the BBB contribute to the progression of disease using sequencing, mouse models, and blood-brain barrier assays.

ALI ERTURK, PH.D., HELMHOLTZ MUNICH

• Develop visualization techniques to assess the accessibility of different molecular tracers through the different barriers in the brain.

FANNY HERISSON, M.D., PH.D., HARVARD MEDICAL SCHOOL / MASSACHUSETTS GENERAL HOSPITAL

• Study the role of channels in the skull in assisting the exit and entry of immune cells and molecules between the periphery and compartments in the meninges.

SE HOON CHOI, PH.D., HARVARD MEDICAL SCHOOL/MASSACHUSETTS GENERAL HOSPITAL, and ROGER KAMM, PH.D., MASSACHUSETTS INSTITUTE OF TECHNOLOGY

• Three-dimensional cell culture models of Alzheimer’s disease
• Micro-fluidic systems that can measure transport across the blood-brain barrier.
• The development of different model systems that together recapitulate transport along the blood-CSF-lymph pathways of the brain.