John Dirk Nieland

Aquaporins in the Spinal Cord

Aquaporins (AQPs) are water channel proteins robustly expressed in the central nervous system (CNS). A number of previous studies described the cellular expression sites and investigated their major roles and function in the brain and spinal cord. Among thirteen different mammalian AQPs, AQP1 and AQP4 have been mainly studied in the CNS and evidence has been presented that they play important roles in the pathogenesis of CNS injury, edema and multiple diseases such as multiple sclerosis, neuromyelitis optica spectrum disorders, amyotrophic lateral sclerosis, glioblastoma multiforme, Alzheimer’s disease and Parkinson’s disease. The objective of this review is to highlight the current knowledge about AQPs in the spinal cord and their proposed roles in pathophysiology and pathogenesis related to spinal cord lesions and injury.

Blocking of carnitine palmitoyl transferase 1 potently reduces stress-induced depression in rat highlighting a pivotal role of lipid metabolism

Major depressive disorder is a complex and common mental disease, for which the pathology has not been elucidated. The purpose of this study is to provide knowledge about the importance of mitochondrial dysfunction, dysregulated lipid metabolism and inflammation. Mitochondrial carnitine palmitoyl transferase 1a (CPT1a) is a key molecule involved in lipid metabolism and mutations in CPT1a causing reduced function is hypothesized to have a protective role in the development of depression. Moreover, CPT1a is found to be upregulated in suicide patients with history of depression. Therefore, we hypothesized that inhibition of CPT1a activity can be developed as an innovative treatment strategy for depression. Stress exposure combined with different pharmacological treatment regimens; Etomoxir, CPT1 blocker, and Escitalopram, a favoured antidepressant drug, was applied in state-of-the-art chronic mild stress model. Etomoxir treatment induced statistical significant reduction of anhedonic behavior compared to vehicle treatment (p < 0.0001) and reversed depression-like phenotype in 90% of the rats (p = 0.0007), whereas Escitalopram only proved 57% efficacy. Moreover, Etomoxir revealed downregulation of interferon-γ, interleukin-17α and tumor necrosis factor-α. This indicate that alteration in metabolism is pivotal in the pathogenesis of depression, since CPT1 blockage is highly efficient in treating anhedonia and inflammation, thereby opening up for a novel class of antidepressant medication.

Identification of brain antigens recognized by autoantibodies in experimental autoimmune encephalomyelitis-induced animals treated with etomoxir or interferon-β

Multiple sclerosis (MS) is a neurodegenerative autoimmune disease, where chronic inflammation plays an essential role in its pathology. A feature of MS is the production of autoantibodies stimulated by an altered-peptide-ligand response and epitope spreading, resulting in loss of tolerance for self-proteins. The involvement of autoantibodies in MS pathogenesis has been suggested to initiate and drive progression of inflammation; however, the etiology of MS remains unknown. The effect of etomoxir and interferon-β (IFN-β) was examined in an experimental-autoimmune-encephalomyelitis (EAE) model of MS. Moreover, the impact of etomoxir and IFN-β on recognition of brain proteins in serum from EAE rats was examined with the purpose of identifying the autoantibody reactivities involved in MS. Animals treated with etomoxir on day 1 exhibited a statistically significantly lower disease score than animals treated with IFN-β (on day 1 or 5) or placebo. Etomoxir treatment on day 5 resulted in a significantly lower disease score than IFN-β treatment on day 1. After disease induction antibodies was induced to a broad pallet of antigens in the brain. Surprisingly, by blocking CPT1 and therewith lipid metabolism several alterations in the antibody response was observed suggesting that autoantibodies play a role in the EAE animal model.

Proteomics-driven design of endothelial stress-based protein array for disease prognostics: applied to plasma and cerebrospinal fluid

Extracellular vesicles (EVs) have a demonstrated involvement in modulating the immune system. It has been proposed that EVs could be used as biomarkers for detection of inflammatory and immunological disorders. Consequently, it is of great interest to investigate EVs in more detail with focus on immunological markers. In this study, five major leukocyte subpopulations and the corresponding leukocyte-derived EVs were phenotyped with focus on selected immunological lineage-specific markers and selected vesicle-related markers. The leukocyte-derived EVs displayed phenotypic differences in the 34 markers investigated. The majority of the lineage-specific markers used for identification of the parent cell types could not be detected on EVs released from monocultures of the associated cell types. In contrast, the vesicular presentation of CD9, CD63, and CD81 correlated to the cell surface expression of these markers, however, with few exceptions. Furthermore, the cellular expression of CD9, CD63, and CD81 varied between leukocytes present inwhole blood and cultured leukocytes. In summary, these data demonstrate that the cellular and vesicular presentation of selected lineage-specific and vesicle-relatedmarkersmay differ, supporting the accumulating observations that sorting of molecular cargo into EVs is tightly controlled.ISEV2016 is organized by The Local Organizing Committee Chair Edit I Buzás (Hungary), Aled Clayton (United Kingdom), Dolores Di Vizio (USA), Juan Manuel Falcon-Perez (Spain), Guido Jenster (The Netherlands), Lorraine O’Driscoll (Ireland), Yong Song Gho (South Korea), Marjolein van Driel (The Netherlands), Hans van Leeuwen (The Netherlands), Guillaume van Niel (France), Marca HM Wauben (The Netherlands), Kenneth W Witwer (USA), María Yáñez-Mó (Spain) Together with the Executive ISEV Board (2014 – 2016) President: Jan Lötvall Secretary General: Clotilde Théry Interim Treasurer: Kenneth W Witwer Executive Chair Science / Meetings: Marca Wauben Executive Chair Education: Yong Song Gho Executive Chair Communication: Andrew Hill Members at Large: Peter Quesenberry, Kenneth W Witwer, Susmita Sahoo, Dolores Di Vizio, Chris Gardiner, Edit I Buzás, Hidetoshi Tahara, Suresh Mathivanan, Igor Kurochkin

CPT1a mutation leads the way for new medication for the treatment of multiple sclerosis

227a Results of MOMENTUM, a randomised, doubleblind, placebo-controlled, phase 2 trial with MT-1303, a novel selective sphingosine 1-phosphate receptor 1 (S1P1) modulator, in relapsing-remitting MS L. Kappos1, D. Arnold2, A. Bar-Or2, J. Camm3, T. Derfuss1, B. Kieseier4, T. Sprenger1, K. Greenough5, P. Ni6, T. Harada6 1Neurology, University Hospital Basel, Basel, Switzerland, 2McGill University, Montreal, QC, Canada, 3St. George’s Hospital Medical Center, London, United Kingdom, 4Neurologische Klinik, Heinrich-Heine Universität, Duesseldorf, Germany, 5Mitsubishi Tanabe Pharma CorporationMitsubishi Tanabe Pharma Europe Ltd., 6Mitsubishi Tanabe Pharma Europe Ltd., London, United Kingdom