Abstract:
:Alterations in sphingolipid metabolism are described to contribute to various neurological disorders. We here determined the expression of enzymes involved in the sphingomyelin cycle and their products in postmortem brain tissue of multiple sclerosis (MS) patients. In parallel, we investigated the effect of the sphingosine-1 receptor agonist Fingolimod (Gilenya(®)) on sphingomyelin metabolism in reactive astrocytes and determined its functional consequences for the process of neuro-inflammation. Our results demonstrate that in active MS lesions, marked by large number of infiltrated immune cells, an altered expression of enzymes involved in the sphingomyelin cycle favors enhanced ceramide production. We identified reactive astrocytes as the primary cellular source of enhanced ceramide production in MS brain samples. Astrocytes isolated from MS lesions expressed enhanced mRNA levels of the ceramide-producing enzyme acid sphingomyelinase (ASM) compared to astrocytes isolated from control white matter. In addition, TNF-α treatment induced ASM mRNA and ceramide levels in astrocytes isolated from control white matter. Incubation of astrocytes with Fingolimod prior to TNF-α treatment reduced ceramide production and mRNA expression of ASM to control levels in astrocytes. Importantly, supernatants derived from reactive astrocytes treated with Fingolimod significantly reduced transendothelial monocyte migration. Overall, the present study demonstrates that reactive astrocytes represent a possible additional cellular target for Fingolimod in MS by directly reducing the production of pro-inflammatory lipids and limiting subsequent transendothelial leukocyte migration.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
van Doorn R,Nijland PG,Dekker N,Witte ME,Lopes-Pinheiro MA,van het Hof B,Kooij G,Reijerkerk A,Dijkstra C,van van der Valk P,van Horssen J,de Vries HEdoi
10.1007/s00401-012-1014-4subject
Has Abstractpub_date
2012-09-01 00:00:00pages
397-410issue
3eissn
0001-6322issn
1432-0533journal_volume
124pub_type
杂志文章abstract::Nine dogs with canine distemper encephalitis (CDE) were examined with immunological techniques including demonstration of antibodies against canine distemper virus (CDV) in the serum and against myelin basic protein (MBP) in serum and in CSF. Mitogen stimulation tests of lymphocytes were also done. The brains were exa...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00691174
更新日期:1982-01-01 00:00:00
abstract::We evaluated by in situ nick end labeling the presence of apoptotic glial cells in the spinal cord of rats which have sustained a moderate and severe compression injury at the level of T8-9, resulting in a severe but reversible paraparesis and irreversible paraplegia, respectively. In a previous investigation we found...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010051112
更新日期:1999-11-01 00:00:00
abstract::Histamine dihydrochloride (10 micrograms of 500 micrograms/ml) was infused during 1 min into the lateral cerebral ventricle of rats, which resulted in a significant stimulation of pinocytosis in the endothelial cells. Systemic injections of mepyramine or metiamide could not prevent this activation. In contrast, raniti...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00686387
更新日期:1988-01-01 00:00:00
abstract::In recent years, we have used a variety of tau immunological markers combined with the dye thiazin red (TR), an accurate marker to differentiate the fibrillar from the nonfibrillar state of both amyloid-beta and tau in Alzheimer's disease (AD). In this study, we used TR as a potential diagnostic marker of AD in frozen...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-008-0431-x
更新日期:2008-11-01 00:00:00
abstract::The left and right recurrent laryngeal nerves and peroneal nerves from two groups of foals, one less than 1 month of age and the other 6 months of age, were examined by light and electron microscopy. While there was no evidence of fiber loss on light microscopy, occasional onion bulbs, regenerating clusters and swolle...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00227825
更新日期:1992-01-01 00:00:00
abstract::The occurrence and topographic analysis of granulovacuolar degeneration (GVD) in the hippocampal cortex of mentally normal controls (75 cases) and patients with Alzheimer's dementia (AD; 17 cases which included Alzheimer's disease and senile dementia of Alzheimer type), multi-infarct dementia (MID; 16 cases), Pick's d...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00304627
更新日期:1992-01-01 00:00:00
abstract::A patient with mixed gonadal dysgenesis showed glove and stocking-type sensory impairment and slowing of motor and sensory nerve conduction. Sural nerve biopsy revealed minifascicular formation with decreased density of myelinated fibers. As far as we are aware, this is the first report of polyneuropathy with minifasc...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010051085
更新日期:1999-09-01 00:00:00
abstract::Synemin is a member of the intermediate protein superfamily. Previous studies in avian and rodent skeletal and cardiac muscles have demonstrated that synemin localises at the Z-band, where it associates with desmin and alpha-actinin. In the present study, the distribution of synemin was examined using immunohistochemi...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-003-0695-0
更新日期:2003-07-01 00:00:00
abstract::A 9-year-old male patient developed a germ cell tumor in the right basal ganglia which secreted beta-human chorionic gonadotropin (beta-HCG) and caused precocious puberty. Histology and immunohistochemical staining for placental alkaline phosphatase (PLAP), alpha-fetoprotein (alpha-FP), and beta-HCG showed a mixed pop...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687797
更新日期:1988-01-01 00:00:00
abstract::A macrosomic male infant with multiple malformations survived for 4 days. His external dysplasias comprised macrocephalus, cheilopalatoschisis, auricular anomalies, and unilateral hexadactyl; his internal dysplasias included cysts of kidneys and pancreas, and a patent foramen ovale. The child had frequent generalized ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690449
更新日期:1980-01-01 00:00:00
abstract::Both protein kinases and phosphoprotein phosphatases are important components of signal transduction systems in cells. Recent studies in Alzheimer's disease (AD) have shown abnormal protein phosphorylation in the cortex suggesting an alteration in these enzymes. In the present study, an antibody against CD45 was used ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00294425
更新日期:1991-01-01 00:00:00
abstract::A study was undertaken to determine the pathological significance of previously unrecognized intracytoplasmic eosinophilic inclusions (IEIs) in ependymoma. The study group consisted of 58 ependymomas, all of which were pathologically characterized and graded according to the 1993 WHO classification. Electron microscop...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/pl00007427
更新日期:2000-02-01 00:00:00
abstract::We present the neuropathological findings in a female patient with clinically definite multiple sclerosis (MS), who at autopsy had multifocal amyloid deposits in the white matter of the brain without other signs of amyloidosis. The patient had relapsing/remitting MS between the ages of 26 and 45, and during her last 1...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s004010050604
更新日期:1997-02-01 00:00:00
abstract::Following maternal chicken pox in the 14th week of pregnancy, a male infant was born with low birth weight, muscle wasting and limb contractures, hypotonia and areflexia. A rising titre of varicella-zoster-specific IgM (by enzyme-linked immunoabsorbent assay) confirmed congenital infection, and electromyogram showed w...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687781
更新日期:1988-01-01 00:00:00
abstract::The brain of a 69-year-old man exhibited extensive granulomatous inflammation in the walls of arteries in the leptomeninges, associated with amyloid deposition in the media of the involved arteries. The extracranial arteries exhibited neither granulomatous inflammation nor amyloid deposition in their walls. ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00686094
更新日期:1986-01-01 00:00:00
abstract::In almost all of the earlier reported cases of Kufs' disease, the adult form of ceroid lipofuscinosis, the diagnosis was ascertained by cerebral tissue examination, while peripheral biopsy examination revealed an apparent poor diffusion of specific lipofuscinic deposits, the finger print profiles (FPs). We report the ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050866
更新日期:1998-07-01 00:00:00
abstract::The expression of glial fibrillary acidic protein (GFAP), vimentin, S-100 protein (S-100), HNK-1, myelin basic protein (MBP) and fibronectin was investigated immunohistochemically in 51 ethylnitrosourea (ENU)-induced neurinomas of the rat. Additionally, 90 transplantation tumors derived from ENU-induced neurinomas and...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00310927
更新日期:1991-01-01 00:00:00
abstract::Human recombinant tumor necrosis factor-alpha (rTNF-alpha) was administered to normal Fischer 344 rats by stereotaxic intracerebral (IC) injection. Animals received a single injection of either 6 x 10(4) U rTNF-alpha or excipient in their right parietal lobe. Others received three consecutive daily injections of eithe...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00304638
更新日期:1992-01-01 00:00:00
abstract::Adult rabbits were subjected to 4.5 Gy of whole-blody or brain alone gamma-irradiation, and their hippocampus was examined with the light and electron microscope. Pycnotic cells were found at the base of the granular layer of the dentate gyrus in the so-called subgranular zone, as soon as 3 h after irradiation, and we...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690520
更新日期:1979-12-01 00:00:00
abstract::Activation of the MAPK signaling pathway has been shown to be a unifying molecular feature in pilocytic astrocytoma (PA). Genetically, tandem duplications at chromosome 7q34 resulting in KIAA1549-BRAF fusion genes constitute the most common mechanism identified to date. To elucidate alternative mechanisms of aberrant ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-011-0817-z
更新日期:2011-06-01 00:00:00
abstract::The mechanism of inflammatory demyelination in canine distemper encephalitis (CDE) is uncertain but macrophages are thought to play an important effector role in this lesion. Serum and cerebrospinal fluid (CSF), containing anti-canine distemper virus and anti-myelin antibodies from dogs with CDE were tested for their ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00688176
更新日期:1989-01-01 00:00:00
abstract::Using a fluorescent antibody technique, sections of the brains of patients with senile dementia or Alzheimer's disease containing senile plaques were treated with rabbit antihuman immunoglobulins labelled with FITC (fluorescein isothiocyanate, BBL). The senile plaques and the cerebral amyloid angiopathy (drusige Entar...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00689569
更新日期:1975-08-11 00:00:00
abstract::Chronic traumatic encephalopathy (CTE) is a progressive degenerative disorder associated with repetitive traumatic brain injury. One of the primary defining neuropathological lesions in CTE, based on the first consensus conference, is the accumulation of hyperphosphorylated tau in gray matter sulcal depths. Post-morte...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-017-1686-x
更新日期:2017-03-01 00:00:00
abstract::Paired helical filaments (PHF) were isolated from autopsied brain of cases of Alzheimer dementia, and their polypeptides were identified with monoclonal antibodies to PHF by Western blots. The PHF polypeptide profile consisted of several bands with a size difference of less than 5 kilodalton (kDa) between adjacent ban...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00690830
更新日期:1985-01-01 00:00:00
abstract::Remyelination in multiple sclerosis (MS) lesions often remains incomplete despite the presence of oligodendrocyte progenitor cells (OPCs). Amongst other factors, successful remyelination depends on the phagocytic clearance of myelin debris. However, the proteins in myelin debris that act as potent and selective inhibi...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-015-1521-1
更新日期:2016-02-01 00:00:00
abstract::Abundant proliferation of cells having the histologic and tinctorial features of microglia, were seen in the brain of 34-year old man who suffered cardiac arrest 10 days before death and whose bone marrow was nearly totally depleted of white-blood-cell precursors. It is suggested, that in adult human brains there are ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00691588
更新日期:1978-09-15 00:00:00
abstract::The mechanisms underlying neurodegenerative diseases are the outcome of pathological alterations of evolutionary conserved molecular and cellular cascades. For this reason, Drosophila and C. elegans serve as useful model systems to study various aspects of neurodegenerative diseases. Here, we introduce the advantageou...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-010-0689-7
更新日期:2010-08-01 00:00:00
abstract::The accumulation of calcium in the hippocampal and thalamic vascular endothelium and the perivascular space was detected histochemically by means of the pyroantimonate technique 30, 60 and 120 min after systemic kainic acid administration. An increased number of calcium pyroantimonate deposits was found in the endothe...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00685971
更新日期:1986-01-01 00:00:00
abstract::N-Methyl-D-aspartate (NMDA) antagonists cause neuronal vacuolation in the posterior cingulate and retrosplenial cortex of the rat. Because the nature of neuronal pathologic changes due to NMDA antagonists may affect the potential clinical use of this class of drugs, we undertook experiments to define the nature and ti...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00386248
更新日期:1994-01-01 00:00:00
abstract::During corticogenesis, neurons adopt different migration pathways to reach their final position. The precursors of pyramidal neurons migrate radially, whereas most of the GABA-containing interneurons are generated in the ventral telencephalon and migrate tangentially into the neocortex. Then, they use a radial migrati...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-010-0692-z
更新日期:2010-10-01 00:00:00