The Choroid Plexus as an Immune-Sensor for the Brain:Implications to Neurological Disease

Joana Palha, Ph.D. and Margarida Correia-Neves, Ph.D.

University of Minho

Funded in September, 2007: $145000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Does the Brain Use a Privileged Pathway to Sense Inflammation Occurring in the Rest of the Body?

The investigators will study the role of the brain’s choroid plexus in inflammatory disorders of the central nervous system (CNS), including autoimmune multiple sclerosis (MS).  

The choroid plexus is a single layer of cells that forms a protective lining for the brain’s four ventricles (cavities), which are enlargements of the central canal of the spinal cord. The choroid plexus produces at least two-thirds of the cerebrospinal fluid (CSF) that travels between the spinal cord and brain, providing nutrients and removing waste. Conditions that influence the production of proteins by the choroid plexus, or that alter the permeability of this barrier, might be implicated in brain diseases. In fact, the researchers’ preliminary evidence suggests that the choroid plexus senses inflammation in the periphery (the rest of the body), and transmits signals about this to the brain via the CSF. The choroid plexus is equipped to do this, since it is an active site of protein synthesis, and possesses various receptors for molecules involved in the inflammatory process. 

Specifically, the researchers’ preliminary data suggest that acute inflammation leads genes in the choroid plexus to modify their production of proteins involved in the immune inflammatory process.  Since systemic inflammation is known to be involved in several neurological diseases, including MS, the researchers hypothesize that peripheral inflammation triggers MS onset via the choroid plexus.  They will study the animal model of MS, called EAE (experimental allergic encephalomyelitis), to: 1) determine how the choroid plexus responds to peripheral chronic inflammation by analyzing the proteins produced by choroid plexus genes; and 2) identify the genes whose proteins are most altered in EAE, and determine the proteins’ effects on brain cell activation and survival.  The results may show how altered choroid plexus-derived proteins influence the brain’s response to peripheral inflammation, and how these changes relate to damage produced by EAE.

Significance: If the study demonstrates that the choroid plexus is the interface for inflammatory signals to reach the brain and contribute to the onset, remissions, and exacerbations of animal model of MS, the findings may lead to novel therapies to treat this autoimmune disease.

ABSTRACT

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The Choroid Plexus as an Immune-Sensor for the Brain: Implications for Neurological Disease

Although there is growing evidence of interactions between systemic inflammation, the brain, and neurological disease, the precise mechanisms by which the peripheral immune system transmits signals to the brain are largely unknown. We are interested in better understanding the role of the choroid plexus (CP)/cerebrospinal fluid (CSF)/brain barrier as a privileged pathway of communication between the periphery and the brain.

The CP is an epithelial cell monolayer located within the brain ventricles, responsible for the production of at least 2/3 of the CSF. The CSF fills all brain ventricles and the subarachnoid space and, therefore, is in close contact with a vast region of the brain parenchyma. In spite of the knowledge that blood flow through the CP is up to ten times higher than that in other brain regions, and that the CP membrane surface area of contact with the brain is about half of that formed by the blood-brain barrier, few studies have addressed the CP involvement in brain inflammatory processes.

In addition to producing CSF, the CP is also an active site of protein synthesis and possesses various receptors relevant in the inflammatory process, including that for the bacterial lipopolysacharide and others for neurotransmitters, growth factors, and hormones. Therefore, the CP is well equipped to sense peripheral inflammatory stimuli and to transmit signals via the CSF to the brain parenchyma. This proposal stems from preliminary data showing that an acute inflammatory systemic stimulus leads to modifications on CP gene expression of constitutively expressed proteins and immuno-modulatory molecules.

Peripheral systemic inflammation is known to play an important role in neurological diseases such as multiple sclerosis (MS). MS is a chronic inflammatory disease of the central nervous system (CNS) characterized by focal areas of demyelination, reactive gliosis, and axonal damage. MS is considered a T-cell mediated autoimmune disease mostly associated with Th1, and more recently with Th17 cells. Evidence suggests that peripheral inflammatory stimulus might trigger the onset of the disease. For instances, relapses in MS occur often after a strong inflammatory systemic stimulus. Administration of anti-inflammatory/immunomodulator drugs leads to improvement of the symptoms when the disease is established or prevention of disease onset in animal models.

How the inflammatory stimuli reach the brain is a current active area of research. Despite the fact that the CP is on the interface between the CNS and the periphery, and thus in a privileged position to mediate interactions between the periphery and the CNS, little attention has been devoted to the CP in neurological disorders. It is also not known how much the inflammation associated with neurological diseases influences CP gene expression and, consequently, CSF composition and ultimately disease onset and/or progression. It is also unclear how the CP responds or might be a target for novel therapeutic strategies. Some of the molecules found to be altered in the CSF of MS patients might result from altered expression in the CP. Of notice and in the context of the present proposal, it has also been recently suggested that migration of T cells into the brain, a characteristic feature of MS pathology, first occurs through the meninges and the CP.

We propose to characterize the CP gene expression profile in response to systemic chronic inflammation and in the course of the different clinical phases of MS; this might reveal novel mechanisms of disease onset and progression. The project has three Specific Aims:

1. To characterize, using microarrays, the CP’s gene expression profile in response to chronic systemic inflammation and compare with that of the experimental autoimmune encephalomyelitis (EAE) animal model of MS.

2. To examine the effect of an anti-inflammatory/immunomodulator drug on the CP gene expression profile in the EAE model of MS.

3. To study, in vitro, the effect of particular proteins produced by the CP, and that are up-regulated both during systemic chronic inflammation and in the acute phase of EAE, on neuronal and microglia survival and activation.

INVESTIGATOR BIOGRAPHIES

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Joana Palha, Ph.D. and Margarida Correia-Neves, Ph.D.

Joana Palha, Ph.D., is an Associate Professor at the School of Health Sciences, University of Minho, Braga, Portugal, and has performed her research in the associated Life and Health Sciences Research Institute (ICVS) since 2001. Her main research interests are neuroimmunology and neuroendocrinology, and how the immune and the endocrine systems influence the onset and progression of diseases affecting/disturbing the central nervous system. The bridge between these two main interests presently resides on the barriers of the brain, the focus of this research project. Dr. Palha has also been involved in projects studying how thyroid hormones influence psychomotor development of newborns and how are they implicated in diseases such as schizophrenia.

Dr. Palha graduated with a degree in Biochemistry fromthe University of Porto, Portugal, in 1991, and defended her Ph.D. in 1995 at the same university. The Ph.D. project, performed at Columbia University, NY, aimed at studying the role of a major thyroid hormone carrier protein in thyroid hormone homeostasis. She then moved, for a brief postdoc to the New York University Medical Center, on a project studying presenilins in Alzheimer’s disease. In 1996, Dr. Palha returned to Portugal, to become an Assistant Professor at the Instituto Superior de Ciências da Saúde, Paredes, Portugal, and in 1999 became an Assistant Investigator at the Institute for Molecular and Cell Biology, University of Porto. In 2001 she joined the newly-formed School of Health Sciences/ICVS, University of Minho, where her current research is being developed. In addition, Dr. Palha is actively involved in teaching medical students about the biochemistry of various organic and functional body systems.

Margarida Correia-Neves, Ph.D., is an Assistant Professor at the School of Health Sciences, University of Minho, Braga, Portugal, and has performed her research in the associated Life and Health Sciences Research Institute (ICVS) since 2006. Her main current research interest is the immune response to infection by mycobacteria, particularly the role of T cells and cytokines. Recently, Dr. Correia-Neves became interested in the role of the immune system in behavioral disorders such as depression and anxiety, and is now addressing how immunomodulators, such as cytokines and others at the barriers of the brain, can contribute to diseases such as multiple sclerosis.

Dr. Correia-Neves obtained the degree of Veterinary Medicine at the University of Lisbon, Portugal, in 1993, and defended her Ph.D. thesis on T cell differentiation at the University Louis Pasteur, Strasbourg, France in 1999. After one year dedicated to bird watching and photography in India and Nepal, she returned to Portugal in 2001, initially as a postdoctoral fellow and later as an Assistant Investigator at the Institute for Molecular and Cell Biology, University of Porto, where she initiated her work on the immune response to infection. From 2002 to 2005 Dr. Correia-Neves was an Assistant Professor at the Polytechnic Institute in Health Sciences, ISAVE, Fontarcada, Portugal, teaching microbiology to students in health sciences. In 2006, she joined the School of Health Sciences/ICVS, University of Minho, where her current research is being developed. In addition, Dr. Correia-Neves is actively involved in teaching medical students subjects related to immunology and microbiology.