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Experimental animal studies on the function of the p75NTR receptor in MS...

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Title Experimental animal studies on the function of the p75NTR receptor in MS related inflammation and demyelination
Period 06 / 2003 - 06 / 2005
Status Completed
Research number OND1309500
Data Supplier Stichting MS Research

Abstract

The histopathology of MS is mainly characterised by inflammation and demyelination. Whereas the causes and primary events in MS are still unknown, it is clear that immune cells invade the central nervous system (CNS) and instigate demyelination and the death of oligodendrocytes. A number of observations strongly suggest that neurotrophins, in particular nerve growth factor (NGF) via the low affinity neurotrophin receptor, p75NTR, are involved in both processes: - MS patients show a dramatic increase in the level of the neurotrophin NGF in the cerebrospinal fluid (CSF) during acute attacks; during remission the NGF levels in CSF markedly decrease. Increased levels of NGF have also been observed in the brain of rats with experimental allergic encephalomyelitis (EAE), an animal model for MS. - In this animal model for MS, we have observed the expression of the p75NTR receptor at the initial stage of infiltration in cells contributing to the blood brain barrier (BBB), such as endothelial cells, pericytes and perivascular macrophages. - Recent studies have provided evidence that interference in p75NTR/NGF signalling reduces inflammation and subsequently alleviates clinical symptoms in a mouse model for MS. - In MS lesions, oligodendrocytes express the p75NTR receptor, whereas in the normal mature brain and in unaffected brain areas of MS patients, oligodendrocytes do not express this receptor. Some of these p75NTR-positive oligodendrocytes appear to be apoptotic, some, in contrast, seem to contribute to remyelination. Similar observations were done in animal models for MS. - Experimental studies have demonstrated that the p75NTR receptor can be considered as a stress induced receptor, which plays a pivotal role in the ultimate fate of an injured cell. In cells that are severely injured beyond rescue, the p75NTR receptor acts as a death receptor inducing intracellular cascades that lead to a swift and neat way of cell removal via apoptosis. In only lightly affected cells, the p75NTR receptor induces secondary messenger pathways that alter gene transcription leading to adaptation and cell survival. In vitro studies have shown that this stress function of the p75NTR receptor most likely applies for oligodendrocytes. In this research project, we aim to study the significance of the p75NTR receptor in both inflammation and demyelination in MS with the use of two different MS animal models: a. Experimental allergic encephalomyelitis (EAE) is an inflammatory disease of the CNS and is a widely accepted animal model for MS. EAE is induced in genetically susceptible animals by administration of myelin or a myelin fragment in complete Freund's adjuvant. Clinically, the disease follows an acute and monophasic course. The major pathological event, which mimics MS, is the appearance of inflammatory cell infiltrates forming perivascular cuffs consisting of T-cells and macrophages/monocytes. By inducing EAE in transgenic mice that lack the expression of the p75NTR receptor, we aim to answer the following question: How does the p75NTR receptor regulate the permeability of the blood-brain barrier for inflammatory cells? b. Feeding the copper chelator cuprizone to adult mice induces a synchronous consistent demyelination. This demyelination is an early observable event, without damage to other cell types in the CNS other than oligodendrocytes. Removal of cuprizone from the diet results in remyelination. In contrast to the EAE model where the BBB is disrupted and many inflammatory cells are present, the BBB in the cuprizone model is intact and T-cells are completely absent (in general, the only immune cells present in demyelinated areas are microglia/macrophages). Thus the cuprizone model for MS offers an ideal system to study de- and remyelination events independent of the influences of inflammatory cells. By feeding cuprizone to transgenic mice that lack the expression of the p75NTR receptor, we aim to answer the following question: What is the role of the p75NTR receptor in the pathophysiology of oligodendrocytes and what are the consequences for demyelination and remyelination? With these studies we will obtain further insight into the process of MS lesion formation. It may lead to new therapeutical approaches (e.g. interference in NGF/p75NTR-signalling) for MS.

Abstract (NL)

Het onderzoek tracht inzicht te krijgen in de rol van de neurotrofine-receptor, p75NTR, bij het regelen van de doorlaatbaarheid van de bloed-hersenbarrière voor ontstekingscellen in MS. Bovendien willen wij onderzoeken, welke rol p75NTR speelt bij de afbraak van myeline (demyelinatie) en eventueel bij het herstel van myeline (remyelinatie). Achtergrond van het onderzoek: Neurotrofines, stoffen die normaliter de groei van zenuwcellen stimuleren, zijn ook betrokken bij de vorming van MS-laesies in het centrale zenuwstelsel. Dit effect staat vermoedelijk in verband met een verhoogde aanwezigheid van de p75NTR-receptor, een eiwit dat neurotrofines kan binden en de cel hierop kan laten reageren. Ons eerder onderzoek heeft aangetoond dat p75NTR juist in cellen van hersenbloedvaten (endotheelcellen) van MS-patiënten maar ook van EAE muizen (muizen met een MS-achtige ziekte) versterkt aanwezig is. In speciale EAE muizen, die de erfelijke informatie om de p75NTR-receptor te maken missen (p75NTR-deficiënte muizen), hebben wij meer ontstekingscellen gevonden. Onze hypothese was daarom dat de p75NTR-receptor tijdens ontstekingsprocessen (zoals bij EAE en MS) misschien wel een positieve rol speelt door het overschrijden van de bloed-hersenbarrière door schadelijke ontstekingscellen tegen te houden. Naast de aanwezigheid van p75NTR in MS-bloedvatcellen hebben wij deze receptor ook aangetroffen in sommige stervende myelinevormende cellen (oligodendrocyten) in een ander diermodel voor MS, het cuprizone-model. In dit diermodel krijgen muizen een zeer kleine hoeveelheid van cuprizone, een stof die giftig is voor oligodendrocyten, in het voedsel. Het afsterven van de oligodendrocyten leidt tot het verloren gaan van de myeline rondom zenuwvezels. Omdat bekend is dat p75NTR onder sommige omstandigheden actief celdood kan veroorzaken, wilden wij onderzoeken of die receptor ook echt een noodzakelijke rol speelt in het doodgaan van oligodendrocyten of dat oligodendrocyten misschien toch ook in de afwezigheid van p75NTR afsterven in het cuprizone-diermodel voor MS.

Related organisations

Related people

Researcher Dr. B.M. Küst
Project leader Dr. J.C.V.M. Copray

Classification

A70000 Public health and health care
D21500 Histology, cell biology
D21700 Physiology
D23230 Neurology, otorhinolaryngology, opthalmology

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