392 results on '"Tolnay, M"'
Search Results
152. TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy.
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DiFrancesco JC, Novara F, Zuffardi O, Forlino A, Gioia R, Cossu F, Bolognesi M, Andreoni S, Saracchi E, Frigeni B, Stellato T, Tolnay M, Winkler DT, Remida P, Isimbaldi G, and Ferrarese C
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- Adult, Cell Line, Cell Nucleus metabolism, Cell Nucleus pathology, Cytosol metabolism, Cytosol pathology, DNA Mutational Analysis, Exodeoxyribonucleases metabolism, Fibroblasts metabolism, Fibroblasts pathology, Follow-Up Studies, Hereditary Central Nervous System Demyelinating Diseases drug therapy, Hereditary Central Nervous System Demyelinating Diseases metabolism, Hereditary Central Nervous System Demyelinating Diseases pathology, Humans, Magnetic Resonance Imaging, Male, Microscopy, Confocal, Phosphoproteins metabolism, Retinal Diseases drug therapy, Retinal Diseases metabolism, Retinal Diseases pathology, Tomography, X-Ray Computed, Vascular Diseases drug therapy, Vascular Diseases metabolism, Vascular Diseases pathology, Exodeoxyribonucleases genetics, Frameshift Mutation, Hereditary Central Nervous System Demyelinating Diseases genetics, Phosphoproteins genetics, Retinal Diseases genetics, Vascular Diseases genetics
- Abstract
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.
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- 2015
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153. Amyloid-β in the Cerebrospinal Fluid of APP Transgenic Mice Does not Show Prion-like Properties.
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Skachokova Z, Sprenger F, Breu K, Abramowski D, Clavaguera F, Hench J, Staufenbiel M, Tolnay M, and Winkler DT
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- Alzheimer Disease pathology, Amyloidosis metabolism, Animals, Hippocampus pathology, Humans, Immunohistochemistry, Mice, Inbred C57BL, Mice, Transgenic, Alzheimer Disease cerebrospinal fluid, Amyloid beta-Peptides administration & dosage, Amyloid beta-Peptides cerebrospinal fluid, Hippocampus metabolism, Prions metabolism
- Abstract
Early diagnosis of Alzheimer`s disease (AD) is currently difficult and involves a complex approach including clinical assessment, neuroimaging, and measurement of amyloid-β (Aβ) and tau levels in cerebrospinal fluid (CSF). A better mechanistic understanding is needed to develop more accurate and even presymptomatic diagnostic tools. It has been shown that Aβ derived from amyloid-containing brain tissue has prion-like properties: it induces misfolding and aggregation of Aβ when injected into human amyloid precursor protein (APP) transgenic mice. In contrast, Aβ in the CSF has been less studied, and it is not clear whether it also exhibits prion-like characteristics, which might provide a sensitive diagnostic tool. Therefore, we collected CSF from APP transgenic mice carrying the Swedish mutation (APP23 mice), and injected it intracerebrally into young mice from the same transgenic line. We found that CSF derived Aβ did not induce increased β-amyloidosis, even after long incubation periods and additional concentration. This suggests that Aβ present in the CSF does not have the same prion-like properties as the Aβ species in the brain.
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- 2015
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154. Prion-like mechanisms in the pathogenesis of tauopathies and synucleinopathies.
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Goedert M, Falcon B, Clavaguera F, and Tolnay M
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- Humans, Neurodegenerative Diseases etiology, Neurodegenerative Diseases pathology, Proteostasis Deficiencies complications, Central Nervous System metabolism, Neurodegenerative Diseases metabolism, Prions metabolism, alpha-Synuclein metabolism, tau Proteins metabolism
- Abstract
Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the abnormal aggregation of a small number of intracellular proteins, with tau and α-synuclein being the most commonly affected. Until recently, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. It is now believed that protein aggregates form in a small number of brain cells, from which they propagate intercellularly through templated recruitment, reminiscent of the mechanisms by which prions spread through the nervous system.
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- 2014
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155. U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.
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Lee HZ, Miller BW, Kwitkowski VE, Ricci S, DelValle P, Saber H, Grillo J, Bullock J, Florian J, Mehrotra N, Ko CW, Nie L, Shapiro M, Tolnay M, Kane RC, Kaminskas E, Justice R, Farrell AT, and Pazdur R
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- Aged, Antibodies, Monoclonal, Humanized administration & dosage, Chlorambucil administration & dosage, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Prognosis, Survival Rate, United States, United States Food and Drug Administration, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Approval, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval., (©2014 American Association for Cancer Research.)
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- 2014
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156. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity.
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Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, Parhizkar S, Ward MA, Cavallini A, Jackson S, Bose S, Clavaguera F, Tolnay M, Lavenir I, Goedert M, Hutton ML, and O'Neill MJ
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- Animals, Brain metabolism, Disease Models, Animal, Disease Progression, Female, Hippocampus metabolism, Hippocampus pathology, Humans, Immunohistochemistry, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways metabolism, Neural Pathways pathology, Neurofibrillary Tangles metabolism, Random Allocation, Synapses metabolism, Synapses pathology, Tauopathies metabolism, Time Factors, White Matter metabolism, White Matter pathology, tau Proteins genetics, Brain pathology, Neurofibrillary Tangles pathology, Tauopathies pathology, tau Proteins metabolism
- Abstract
Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer's disease, progressive supranuclear palsy, Pick's disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as 'tau propagation' and may explain the stereotypic progression of tau pathology in the brains of Alzheimer's disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.
- Published
- 2014
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157. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice.
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Clavaguera F, Hench J, Lavenir I, Schweighauser G, Frank S, Goedert M, and Tolnay M
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- Animals, Brain pathology, Disease Models, Animal, Humans, Injections, Intraperitoneal, Mice, Mice, Transgenic, Tauopathies pathology, Time Factors, Tauopathies chemically induced, tau Proteins administration & dosage, tau Proteins adverse effects
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- 2014
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158. Intercellular transfer of tau aggregates and spreading of tau pathology: Implications for therapeutic strategies.
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Clavaguera F, Grueninger F, and Tolnay M
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- Animals, Brain immunology, Brain metabolism, Brain pathology, Disease Models, Animal, Humans, tau Proteins genetics, Immunization, Tauopathies drug therapy, Tauopathies metabolism, tau Proteins immunology, tau Proteins metabolism
- Abstract
Filaments made of hyperphosphorylated tau protein are encountered in a group of neurodegenerative disorders termed tauopathies. The most prevalent tauopathy, Alzheimer's disease (AD), additionally presents with extracellular deposits of the amyloid-β peptide (Aβ). Current symptomatic treatments have shown short term benefits in reducing cognitive symptoms as well as behavioral abnormalities in patients with mild to moderate AD but there is still no effective treatment to prevent or reverse AD. For decades, the amyloid cascade hypothesis of AD dominated basic research and focused pharmaceutical interest on Aβ. However, the existence of tauopathies that are devoid of Aβ deposits, together with the discovery of mutations in the tau gene leading to frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17T), confirmed the importance of tau per se in disease. Tau became an interesting disease target in its own right. We will review here recent research on cell-to-cell propagation of tau pathology, which we believe to be central to disease progression, and discuss tau immunotherapy in the light of these findings. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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159. Brain homogenates from human tauopathies induce tau inclusions in mouse brain.
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Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M, Ghetti B, Goedert M, and Tolnay M
- Subjects
- Aged, Aged, 80 and over, Animals, Blotting, Western, Brain pathology, Crosses, Genetic, Female, Humans, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Tissue Extracts administration & dosage, Transplantation, Heterologous, tau Proteins genetics, Brain metabolism, Tauopathies physiopathology, Tissue Extracts pharmacology, tau Proteins metabolism
- Abstract
Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer's disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer's disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.
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- 2013
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160. Human Fc receptor-like 5 binds intact IgG via mechanisms distinct from those of Fc receptors.
- Author
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Franco A, Damdinsuren B, Ise T, Dement-Brown J, Li H, Nagata S, and Tolnay M
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- Antibody Affinity immunology, Cell Line, Cell Membrane metabolism, Epitopes immunology, Epitopes metabolism, Humans, Kinetics, Protein Binding, Protein Interaction Domains and Motifs, Receptors, Cell Surface chemistry, Recombinant Proteins, Immunoglobulin G metabolism, Receptors, Cell Surface metabolism, Receptors, Fc metabolism
- Abstract
Fc receptor-like (FCRL) 5 regulates B cell Ag receptor signaling and has been reported to bind aggregated IgG. Using surface plasmon resonance, we analyzed the interaction of native IgG samples with FCRL5, revealing a complex binding mechanism, where isotype is just one factor. FCRL5 bound IgG1 and IgG4 with ~1 μM KD, whereas the interaction with IgG3 was a magnitude weaker. However, IgG2 samples displayed a wide range of affinities, indicating that additional factors affect binding. We used a panel of 19 anti-FCRL5 mAbs with defined reactivity to identify domains involved in ligand binding. Six mAbs blocked IgG binding, indicating critical roles of FCRL5 domains 1 and 3, as well as epitopes at the domain 1/2 and domain 2/3 boundaries. We found that only glycosylated IgG containing both Fab arms and the Fc region bound with high affinity. Furthermore, the presence of sialic acid in the IgG carbohydrate altered FCRL5 binding. The interaction of IgG and FCRL5 consisted of two kinetic components, suggesting a complex binding mechanism. We established that the IgG-Fc and IgG-F(ab')2 fragments bind FCRL5 independently but with low affinity, revealing the mechanism behind the two-step binding of whole IgG. This complex binding mechanism is distinct from that of Fc receptors, which bind through the Fc. We propose that FCRL5 is a new type of receptor that recognizes intact IgG, possibly enabling B cells to sense Ig quality. Recognition of undamaged IgG molecules by FCRL5 could allow B cells to engage recently produced Abs.
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- 2013
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161. Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice.
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Ozcelik S, Fraser G, Castets P, Schaeffer V, Skachokova Z, Breu K, Clavaguera F, Sinnreich M, Kappos L, Goedert M, Tolnay M, and Winkler DT
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- Animals, Astrocytes drug effects, Astrocytes pathology, Humans, Mice, Mice, Transgenic, Phosphorylation drug effects, Sirolimus therapeutic use, Solubility, Tauopathies metabolism, Tauopathies pathology, Time Factors, tau Proteins chemistry, tau Proteins metabolism, Disease Progression, Sirolimus pharmacology, Tauopathies drug therapy, Tauopathies genetics, tau Proteins genetics
- Abstract
Altered autophagy contributes to the pathogenesis of Alzheimer's disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies.
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- 2013
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162. Propagating sticky matters: an update on "prion-like" templated misfolding in neurodegenerative disorders.
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Frank S and Tolnay M
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- Humans, Neurodegenerative Diseases genetics, PrPC Proteins genetics, Prion Diseases genetics, Prion Diseases transmission, Proteostasis Deficiencies genetics, alpha-Synuclein metabolism, tau Proteins metabolism, Neurodegenerative Diseases pathology, Prion Diseases pathology, Proteostasis Deficiencies pathology
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- 2013
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163. "Prion-like" templated misfolding in tauopathies.
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Clavaguera F, Lavenir I, Falcon B, Frank S, Goedert M, and Tolnay M
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- Animals, Humans, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Prion Diseases genetics, Proteostasis Deficiencies genetics, Proteostasis Deficiencies therapy, Tauopathies genetics, Tauopathies therapy, Prion Diseases metabolism, Proteostasis Deficiencies metabolism, Tauopathies metabolism
- Abstract
The soluble microtubule-associated protein tau forms hyperphosphorylated, insoluble and filamentous inclusions in a number of neurodegenerative diseases referred to as "tauopathies." In Alzheimer's disease, tau pathology develops in a stereotypical manner, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of tau pathology is also a characteristic of argyrophilic grain disease, where the tau lesions spread throughout the limbic system. Significantly, isoform composition and morphology of tau filaments can differ between tauopathies, suggesting the existence of distinct tau strains. Extensive experimental findings indicate that prion-like mechanisms underly the pathogenesis of tauopathies., (© 2013 The Authors; Brain Pathology © 2013 International Society of Neuropathology.)
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- 2013
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164. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy.
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Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT, and Goedert M
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- Animals, Autophagy drug effects, Brain Stem drug effects, Brain Stem metabolism, Cell Survival drug effects, Cell Survival physiology, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration drug therapy, Neurons drug effects, Neurons metabolism, Neurons physiology, Spinal Cord drug effects, Spinal Cord metabolism, Spinal Cord physiology, Tauopathies drug therapy, Transcription Factor TFIIH, Transcription Factors metabolism, Trehalose therapeutic use, tau Proteins genetics, tau Proteins metabolism, Autophagy physiology, Disease Models, Animal, Nerve Degeneration physiopathology, Tauopathies physiopathology, Trehalose pharmacology
- Abstract
The accumulation of insoluble proteins is a pathological hallmark of several neurodegenerative disorders. Tauopathies are caused by the dysfunction and aggregation of tau protein and an impairment of cellular protein degradation pathways may contribute to their pathogenesis. Thus, a deficiency in autophagy can cause neurodegeneration, while activation of autophagy is protective against some proteinopathies. Little is known about the role of autophagy in animal models of human tauopathy. In the present report, we assessed the effects of autophagy stimulation by trehalose in a transgenic mouse model of tauopathy, the human mutant P301S tau mouse, using biochemical and immunohistochemical analyses. Neuronal survival was evaluated by stereology. Autophagy was activated in the brain, where the number of neurons containing tau inclusions was significantly reduced, as was the amount of insoluble tau protein. This reduction in tau aggregates was associated with improved neuronal survival in the cerebral cortex and the brainstem. We also observed a decrease of p62 protein, suggesting that it may contribute to the removal of tau inclusions. Trehalose failed to activate autophagy in the spinal cord, where it had no impact on the level of sarkosyl-insoluble tau. Accordingly, trehalose had no effect on the motor impairment of human mutant P301S tau transgenic mice. Our findings provide direct evidence in favour of the degradation of tau aggregates by autophagy. Activation of autophagy may be worth investigating in the context of therapies for human tauopathies.
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- 2012
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165. News from the powerhouses.
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Frank S and Tolnay M
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- Animals, Disease Models, Animal, Humans, Mitochondrial Diseases genetics, Mitochondrial Diseases metabolism, Mitochondrial Proteins physiology, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Mitochondria physiology, Mitochondrial Diseases physiopathology, Neurobiology trends, Neurodegenerative Diseases physiopathology
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- 2012
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166. Phenotypic variation of autosomal-dominant corticobasal degeneration.
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Jung HH, Bremer J, Streffer J, Virdee K, Spillantini MG, Crowther RA, Brugger P, Van Broeckhoven C, Aguzzi A, and Tolnay M
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- Aphasia, Primary Progressive genetics, Aphasia, Primary Progressive pathology, Aphasia, Primary Progressive psychology, Basal Ganglia Diseases genetics, Basal Ganglia Diseases psychology, Female, Humans, Middle Aged, Nerve Degeneration genetics, Nerve Degeneration psychology, Neurologic Examination, Neuropsychological Tests, Pedigree, Phenotype, Supranuclear Palsy, Progressive genetics, Supranuclear Palsy, Progressive pathology, Supranuclear Palsy, Progressive psychology, Tauopathies genetics, Tauopathies psychology, Basal Ganglia Diseases pathology, Brain pathology, Nerve Degeneration pathology, Tauopathies pathology
- Abstract
Neurodegenerative tauopathies may be inherited as autosomal-dominant disorders with variable clinicopathological phenotypes, and causative mutations in the microtubule-associated protein tau (MAPT) gene are not regularly seen. Herein, we describe a patient with clinically typical and autopsy-proven corticobasal degeneration (CBD). Her mother was diagnosed to have Parkinson's disease, but autopsy showed CBD pathology as in the index patient. The sister of the index patient had the clinical symptoms of primary progressive aphasia (PPA), but no pathology was available to date. Molecular analysis did not reveal any mutation in the MAPT or progranulin (GRN) genes. Our findings illustrate that CBD, progressive supranuclear palsy and PPA may be overlapping diseases with a common pathological basis rather than distinct entities. Clinical presentation and course might be determined by additional, yet unknown, genetic modifying factors., (Copyright © 2012 S. Karger AG, Basel.)
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- 2012
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167. Fc receptor-like 5 promotes B cell proliferation and drives the development of cells displaying switched isotypes.
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Dement-Brown J, Newton CS, Ise T, Damdinsuren B, Nagata S, and Tolnay M
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- Antigen Presentation physiology, Antigenic Variation immunology, B-Lymphocytes metabolism, Humans, Immunoglobulin A biosynthesis, Immunoglobulin G biosynthesis, Immunoglobulin M biosynthesis, Receptors, Antigen, B-Cell biosynthesis, Receptors, Cell Surface genetics, Receptors, Fc, Signal Transduction immunology, B-Lymphocytes cytology, B-Lymphocytes immunology, Cell Differentiation immunology, Cell Proliferation, Immunoglobulin Isotypes physiology, Receptors, Cell Surface physiology
- Abstract
The biological roles of B cell membrane proteins in the FCRL family are enigmatic. FCRL proteins, including FCRL5, were shown to modulate early BCR signaling, although the subsequent, functional consequences of receptor engagement are poorly understood. We found that FCRL5 surface protein itself was induced temporarily upon BCR stimulation of human, naive B cells, indicating precise control over timing of FCRL5 engagement. Cross-linking of FCRL5 on cells induced to express FCRL5 enhanced B cell proliferation significantly. This enhancement required costimulation of the BCR and TLR9, two signals required for optimal proliferation of naive B cells, whereas T cell help in the form of anti-CD40 and IL-2 was dispensable. In addition, we found that FCRL5 stimulation generated a high proportion of cells displaying surface IgG and IgA. Optimal development of cells expressing switched isotypes required T cell help, in addition to stimuli found necessary for enhanced proliferation. Surprisingly, cells that developed upon FCRL5 stimulation simultaneously displayed surface IgM, IgG, and IgA. Cells expressing multiple Ig isotypes were described in hairy cell leukemia, a disease in which FCRL5 is overexpressed. Enhanced proliferation and downstream isotype expression upon FCRL5 stimulation could reflect a physiological role for FCRL5 in the expansion and development of antigen-primed B cells. In addition, FCRL5 may promote growth of malignant cells in hairy cell leukemia and other FCRL5-expressing tumors.
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- 2012
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168. Atypical prion protein conformation in familial prion disease with PRNP P105T mutation.
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Polymenidou M, Prokop S, Jung HH, Hewer E, Peretz D, Moos R, Tolnay M, and Aguzzi A
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- Adult, Base Sequence, Blotting, Western, Brain pathology, Humans, Male, Molecular Sequence Data, Pedigree, Point Mutation, Prion Proteins, Enzyme-Linked Immunosorbent Assay methods, Prion Diseases diagnosis, Prion Diseases genetics, Prions analysis, Prions genetics
- Abstract
Protease-resistant prion protein (PrP(Sc) ) is diagnostic of prion disease, yet its detection is frequently difficult. Here, we describe a patient with a PRNP P105T mutation and typical familial prion disease. Brain PrP(Sc) was undetectable by conventional Western blotting and barely detectable after phosphotungstate precipitation, where it displayed an atypical pattern suggestive of noncanonical conformation. Therefore, we used a novel misfolded protein assay (MPA) that detects PrP aggregates independently of their protease resistance. The MPA revealed the presence of aggregated PrP in similar amounts as in typical sporadic Creutzfeldt-Jakob disease. These findings suggest that measurements of PrP aggregation with the MPA may be potentially more sensitive than protease-based methodologies.
- Published
- 2011
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169. A tissue-specific approach to the analysis of metabolic changes in Caenorhabditis elegans.
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Hench J, Bratić Hench I, Pujol C, Ipsen S, Brodesser S, Mourier A, Tolnay M, Frank S, and Trifunović A
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- Alleles, Animals, Azo Compounds pharmacology, Carbohydrates chemistry, Colorimetry methods, Green Fluorescent Proteins metabolism, Image Processing, Computer-Assisted, Lipids chemistry, Microscopy methods, Microscopy, Electron, Transmission methods, Microscopy, Phase-Contrast, Mitochondria metabolism, Mutation, Oxygen Consumption, Permeability, Phenotype, Tissue Distribution, Caenorhabditis elegans metabolism
- Abstract
The majority of metabolic principles are evolutionarily conserved from nematodes to humans. Caenorhabditis elegans has widely accelerated the discovery of new genes important to maintain organismic metabolic homeostasis. Various methods exist to assess the metabolic state in worms, yet they often require large animal numbers and tend to be performed as bulk analyses of whole worm homogenates, thereby largely precluding a detailed studies of metabolic changes in specific worm tissues. Here, we have adapted well-established histochemical methods for the use on C. elegans fresh frozen sections and demonstrate their validity for analyses of morphological and metabolic changes on tissue level in wild type and various mutant strains. We show how the worm presents on hematoxylin and eosin (H&E) stained sections and demonstrate their usefulness in monitoring and the identification of morphological abnormalities. In addition, we demonstrate how Oil-Red-O staining on frozen worm cross-sections permits quantification of lipid storage, avoiding the artifact-prone fixation and permeabilization procedures of traditional whole-mount protocols. We also adjusted standard enzymatic stains for respiratory chain subunits (NADH, SDH, and COX) to monitor metabolic states of various C. elegans tissues. In summary, the protocols presented here provide technical guidance to obtain robust, reproducible and quantifiable tissue-specific data on worm morphology as well as carbohydrate, lipid and mitochondrial energy metabolism that cannot be obtained through traditional biochemical bulk analyses of worm homogenates. Furthermore, analysis of worm cross-sections overcomes the common problem with quantification in three-dimensional whole-mount specimens.
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- 2011
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170. Rapid cerebral amyloid binding by Aβ antibodies infused into β-amyloid precursor protein transgenic mice.
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Winkler DT, Abramowski D, Danner S, Zurini M, Paganetti P, Tolnay M, and Staufenbiel M
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- Age Factors, Amyloid beta-Peptides cerebrospinal fluid, Animals, Brain immunology, Brain pathology, Female, Humans, Immunoglobulin G administration & dosage, Infusions, Intravenous, Male, Mice, Mice, Transgenic, Plaque, Amyloid immunology, Amyloid beta-Peptides immunology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor genetics, Brain metabolism, Immunoglobulin G immunology, Plaque, Amyloid metabolism
- Abstract
Background: Passive immunization for the treatment of Alzheimer's disease (AD) was rapidly translated into clinical trials. However, basic mechanisms of AD immunotherapy remain only partially understood., Methods: We analyzed the dynamic changes of amyloid-β (Aβ) levels in plasma, brain, and cerebrospinal fluid (CSF) as well as cerebral amyloid binding by Aβ antibody after a single β1-antibody infusion into APP(Swedish) and APP(wildtype) transgenic mice at preplaque and plaque-bearing age., Results: Following intravenous Aβ antibody treatment, plasma Aβ increased rapidly, reaching significantly higher levels in preplaque compared with plaque-bearing mice, whereas cerebral and CSF Aβ remained unchanged. Strikingly, Aβ antibodies exhibited strong cerebral amyloid plaque binding rapidly after intravenous administration in a subset of animals with more severe vascular amyloid., Conclusions: Rapid plasma Aβ increase after Aβ antibody infusion results primarily from stabilization of Aβ. Nevertheless, the smaller plasma Aβ increase in plaque-bearing mice might be of diagnostic use. Importantly, intravenously administered antibodies can rapidly bind to cerebral plaques, potentially facilitated by vascular-amyloid-mediated damage of the blood-brain barrier., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2010
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171. Sarcoma of the sella after radiotherapy for pituitary adenoma.
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Berkmann S, Tolnay M, Hänggi D, Ghaffari A, and Gratzl O
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- Adenoma pathology, Adult, Fibrosarcoma physiopathology, Humans, Male, Pituitary Neoplasms pathology, Skull Base Neoplasms physiopathology, Spinal Cord Neoplasms secondary, Adenoma radiotherapy, Fibrosarcoma etiology, Fibrosarcoma pathology, Pituitary Neoplasms radiotherapy, Radiotherapy adverse effects, Skull Base Neoplasms etiology, Skull Base Neoplasms pathology
- Abstract
Secondary malignancies are infrequent sequelae of pituitary radiotherapy. The goal of the present case study is to analyze clinical features of a selected group of cases to define the special characteristics of these tumors. We report the illustrative case of a 38-year-old man with acromegaly who had transsphenoidal surgery and radiotherapy 7 years before presenting with a sellar high-grade sarcoma. Transsphenoidal and transcranial resection, as well as repeated gamma knife radiosurgery, could not prevent tumor progression and development of meningiosis sarcomatosa. We performed a thorough search of the literature and reviewed numerous publications and reports on primary and secondary sarcomas of the sella. Our search revealed 51 cases of mesenchymal malignancies after sellar radiotherapy. For further analysis, we identified and selected a group of patients based on the criteria for studying radiation-induced tumors as described by Cahan.Compared to the surgically treated group, secondary sarcomas of the sella are more frequent in patients who have had radiotherapy. These tumors occur at normal dose schedules with long latencies. Their growth is very aggressive and they may develop meningiosis sarcomatosa. Until now, no treatment modalities have been able to stop the progression of these neoplasms. Radiation-induced sarcoma is a rare sequela of pituitary radiotherapy. It is important for the treating physician to keep in mind the possibility of post-radiation sarcoma development. Additionally, one must include these tumors into the differential diagnosis in pituitary patients presenting with tumor recurrence more than 5 years after radiotherapy in combination with a secondary lack of hormonal activity.
- Published
- 2010
- Full Text
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172. Gene expression profiling in nerve biopsy of vasculitic neuropathy.
- Author
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Kinter J, Broglio L, Steck AJ, Tolnay M, Fuhr P, Latov N, Kalbermatten D, Sinnreich M, Schaeren-Wiemers N, and Renaud S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biopsy methods, Child, Preschool, Female, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Male, Nuclear Receptor Subfamily 4, Group A, Member 1 genetics, Nuclear Receptor Subfamily 4, Group A, Member 1 metabolism, Peripheral Nervous System Diseases complications, Peripheral Nervous System Diseases genetics, Peripheral Nervous System Diseases metabolism, Sural Nerve immunology, Vasculitis complications, Vasculitis genetics, Vasculitis metabolism, Gene Expression Profiling methods, Gene Expression Regulation physiology, Peripheral Nervous System Diseases pathology, Sural Nerve metabolism, Vasculitis pathology
- Abstract
To investigate molecular mechanisms of peripheral nerve vasculitis, gene expression patterns in archived frozen sural nerve biopsies from patients with vasculitic neuropathy were compared to control nerves by DNA microarray technology. There was a striking upregulation of mRNA of genes involved in immune system processes. Of special interest was the activation of immunoglobulin genes, such as IGLJ3, IGHG3, IGKC, and IGL, and of several chemokines, such as CXCL9 or CCR2. Genes involved in vascular proliferation or remodelling such as CXC31 and AIF were also upregulated. Among the downregulated genes were the Krüppel-Like Transcription Factors KLF2, KLF4 and the nuclear orphan receptor NR4A1 genes known to be involved in endothelial cell activation. Thus, this gene expression profile analysis revealed that in peripheral nerve vasculitis a prominent activation of immune response related genes as well as genes involved in vascular proliferation is taken place, while genes inhibiting endothelial cell activation are down regulated. These data point to interesting mechanistic clues to the molecular pathogenesis of vasculitic neuropathies., (Copyright 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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173. The propagation of prion-like protein inclusions in neurodegenerative diseases.
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Goedert M, Clavaguera F, and Tolnay M
- Subjects
- Animals, Humans, Inclusion Bodies chemistry, Neurodegenerative Diseases genetics, Prion Diseases genetics, Prion Diseases metabolism, Prion Diseases pathology, Prions genetics, Protein Folding, tau Proteins genetics, tau Proteins metabolism, Inclusion Bodies metabolism, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, Prions metabolism
- Abstract
The most common neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the misfolding of a small number of proteins that assemble into ordered aggregates in affected brain cells. For many years, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. Recent research has now shown that cell non-autonomous mechanisms are also important for the pathogenesis of neurodegenerative diseases with intracellular filamentous inclusions. The intercellular transfer of inclusions made of tau, alpha-synuclein, huntingtin and superoxide dismutase 1 has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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- View/download PDF
174. [Induction and spreading of tau pathology in a mouse model of Alzheimer's disease].
- Author
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Clavaguera F, Goedert M, and Tolnay M
- Subjects
- Alzheimer Disease pathology, Animals, Cerebral Cortex metabolism, Cerebral Cortex pathology, Disease Progression, Hippocampus metabolism, Hippocampus pathology, Injections, Mice, Mice, Transgenic, Microscopy, Immunoelectron, Mutation, Neurofibrillary Tangles chemistry, Neurofibrillary Tangles ultrastructure, Protein Isoforms chemistry, Protein Isoforms genetics, Protein Isoforms toxicity, Protein Structure, Tertiary, Silver Staining, Tissue Extracts administration & dosage, Tissue Extracts toxicity, tau Proteins chemistry, tau Proteins genetics, Alzheimer Disease metabolism, Disease Models, Animal, tau Proteins toxicity
- Published
- 2010
- Full Text
- View/download PDF
175. Frontotemporal lobar degeneration: toward the end of conFUSion.
- Author
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Frank S and Tolnay M
- Subjects
- Frontotemporal Lobar Degeneration genetics, Humans, RNA-Binding Protein FUS genetics, Frontotemporal Lobar Degeneration metabolism, Frontotemporal Lobar Degeneration pathology, RNA-Binding Protein FUS metabolism
- Published
- 2009
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176. Loss of hypocretin (orexin) neurons with traumatic brain injury.
- Author
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Baumann CR, Bassetti CL, Valko PO, Haybaeck J, Keller M, Clark E, Stocker R, Tolnay M, and Scammell TE
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Count methods, Female, Humans, Hypothalamus metabolism, Hypothalamus pathology, Intracellular Signaling Peptides and Proteins physiology, Male, Middle Aged, Neuropeptides physiology, Orexins, Pilot Projects, Wakefulness physiology, Brain Injuries metabolism, Brain Injuries pathology, Neurons metabolism, Neurons pathology, Neuropeptides biosynthesis
- Abstract
Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood. Extensive loss of the hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (orexin) causes the severe sleepiness of narcolepsy, and partial loss of these cells may contribute to the sleepiness of Parkinson disease and other disorders. We have found that the number of hypocretin neurons is significantly reduced in patients with severe TBI. This observation highlights the often overlooked hypothalamic injury in TBI and provides new insights into the causes of chronic sleepiness in patients with TBI.
- Published
- 2009
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177. Functionally relevant domains of the prion protein identified in vivo.
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Baumann F, Pahnke J, Radovanovic I, Rülicke T, Bremer J, Tolnay M, and Aguzzi A
- Subjects
- Animals, Cell Membrane metabolism, Genetic Variation, Glycosylphosphatidylinositols chemistry, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Neurotoxins chemistry, Phenotype, Prion Proteins, Prions genetics, Protein Structure, Tertiary, Recombinant Fusion Proteins chemistry, Signal Transduction, Transgenes, Prions chemistry, Prions physiology
- Abstract
The prion consists essentially of PrP(Sc), a misfolded and aggregated conformer of the cellular protein PrP(C). Whereas PrP(C) deficient mice are clinically healthy, expression of PrP(C) variants lacking its central domain (PrP(DeltaCD)), or of the PrP-related protein Dpl, induces lethal neurodegenerative syndromes which are repressed by full-length PrP. Here we tested the structural basis of these syndromes by grafting the amino terminus of PrP(C) (residues 1-134), or its central domain (residues 90-134), onto Dpl. Further, we constructed a soluble variant of the neurotoxic PrP(DeltaCD) mutant that lacks its glycosyl phosphatidyl inositol (GPI) membrane anchor. Each of these modifications abrogated the pathogenicity of Dpl and PrP(DeltaCD) in transgenic mice. The PrP-Dpl chimeric molecules, but not anchorless PrP(DeltaCD), ameliorated the disease of mice expressing truncated PrP variants. We conclude that the amino proximal domain of PrP exerts a neurotrophic effect even when grafted onto a distantly related protein, and that GPI-linked membrane anchoring is necessary for both beneficial and deleterious effects of PrP and its variants.
- Published
- 2009
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178. The molecular basis of frontotemporal dementia.
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Neumann M, Tolnay M, and Mackenzie IR
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- Adenosine Triphosphatases genetics, Cell Cycle Proteins genetics, Dementia pathology, Endosomal Sorting Complexes Required for Transport, Humans, Intercellular Signaling Peptides and Proteins genetics, Mutation, Nerve Tissue Proteins genetics, Progranulins, Valosin Containing Protein, tau Proteins genetics, Dementia genetics, Dementia metabolism
- Abstract
Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Familial FTD has been linked to mutations in several genes, including those encoding the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B). The associated neuropathology is characterised by selective degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration, FTLD), usually with the presence of abnormal intracellular protein accumulations. The current classification of FTLD neuropathology is based on the identity of the predominant protein abnormality, in the belief that this most closely reflects the underlying pathogenic process. Major subgroups include those characterised by the pathological tau, TDP-43, intermediate filaments and a group with cellular inclusions composed of an unidentified ubiquitinated protein. This review will focus on the current understanding of the molecular basis of each of the major FTLD subtypes. It is anticipated that this knowledge will provide the basis of future advances in the diagnosis and treatment of FTD.
- Published
- 2009
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179. Transmission and spreading of tauopathy in transgenic mouse brain.
- Author
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Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, and Tolnay M
- Subjects
- Animals, Blotting, Western, Humans, Immunohistochemistry, Mice, Mice, Transgenic, tau Proteins genetics, tau Proteins metabolism, tau Proteins physiology, Brain metabolism, Brain pathology, Tauopathies genetics, Tauopathies pathology
- Abstract
Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease. In the disease process, neuronal tau inclusions first appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular beta-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. An abundance of tau inclusions, in the absence of beta-amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia. Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein. By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions.
- Published
- 2009
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180. Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.
- Author
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Ludolph AC, Kassubek J, Landwehrmeyer BG, Mandelkow E, Mandelkow EM, Burn DJ, Caparros-Lefebvre D, Frey KA, de Yebenes JG, Gasser T, Heutink P, Höglinger G, Jamrozik Z, Jellinger KA, Kazantsev A, Kretzschmar H, Lang AE, Litvan I, Lucas JJ, McGeer PL, Melquist S, Oertel W, Otto M, Paviour D, Reum T, Saint-Raymond A, Steele JC, Tolnay M, Tumani H, van Swieten JC, Vanier MT, Vonsattel JP, Wagner S, and Wszolek ZK
- Subjects
- Animals, Biomarkers, Dementia complications, Dementia genetics, Dementia physiopathology, Drug Design, Geography, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Models, Biological, Mutation, Niemann-Pick Disease, Type C complications, Niemann-Pick Disease, Type C diagnosis, Niemann-Pick Disease, Type C physiopathology, Parkinson Disease, Postencephalitic complications, Parkinson Disease, Postencephalitic physiopathology, Parkinsonian Disorders pathology, Parkinsonian Disorders physiopathology, Parkinsonian Disorders therapy, Pick Disease of the Brain complications, Pick Disease of the Brain pathology, Protein Serine-Threonine Kinases genetics, Supranuclear Palsy, Progressive complications, Supranuclear Palsy, Progressive diagnosis, Supranuclear Palsy, Progressive physiopathology, Tauopathies pathology, Tauopathies physiopathology, Tauopathies therapy, tau Proteins genetics, Parkinsonian Disorders complications, Tauopathies complications
- Abstract
Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.
- Published
- 2009
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181. Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas.
- Author
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Sivasankaran B, Degen M, Ghaffari A, Hegi ME, Hamou MF, Ionescu MC, Zweifel C, Tolnay M, Wasner M, Mergenthaler S, Miserez AR, Kiss R, Lino MM, Merlo A, Chiquet-Ehrismann R, and Boulay JL
- Subjects
- Amino Acid Sequence, Base Sequence, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Movement physiology, Glioblastoma metabolism, Glioblastoma pathology, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Immunohistochemistry, Molecular Sequence Data, Oligodendroglioma genetics, Oligodendroglioma metabolism, Oligodendroglioma pathology, Promoter Regions, Genetic, Receptor, Notch2 genetics, Receptor, Notch2 metabolism, Response Elements, Signal Transduction, Tenascin biosynthesis, Transcriptional Activation, Brain Neoplasms genetics, Glioblastoma genetics, Immunoglobulin J Recombination Signal Sequence-Binding Protein biosynthesis, Receptor, Notch2 biosynthesis, Tenascin genetics
- Abstract
Tenascin-C (TNC) expression is known to correlate with malignancy in glioblastoma (GBM), a highly invasive and aggressive brain tumor that shows limited response to conventional therapies. In these malignant gliomas as well as in GBM cell lines, we found Notch2 protein to be strongly expressed. In a GBM tumor tissue microarray, RBPJk protein, a Notch2 cofactor for transcription, was found to be significantly coexpressed with TNC. We show that the TNC gene is transactivated by Notch2 in an RBPJk-dependent manner mediated by an RBPJk binding element in the TNC promoter. The transactivation is abrogated by a Notch2 mutation, which we detected in the glioma cell line Hs683 that does not express TNC. This L1711M mutation resides in the RAM domain, the site of interaction between Notch2 and RBPJk. In addition, transfection of constructs encoding activated Notch2 or Notch1 increased endogenous TNC expression identifying TNC as a novel Notch target gene. Overexpression of a dominant negative form of the transcriptional coactivator MAML1 or knocking down RBPJk in LN319 cells led to a dramatic decrease in TNC protein levels accompanied by a significant reduction of cell migration. Because addition of purified TNC stimulated glioma cell migration, this represents a mechanism for the invasive properties of glioma cells controlled by Notch signaling and defines a novel oncogenic pathway in gliomagenesis that may be targeted for therapeutic intervention in GBM patients.
- Published
- 2009
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- View/download PDF
182. A 28-year-old man with headache, visual and aphasic speech disturbances.
- Author
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Frank S, Cordier D, Tolnay M, and Rosenblum MK
- Subjects
- Adult, Antigens, CD34 analysis, Brain Neoplasms complications, Brain Neoplasms metabolism, Gliosarcoma complications, Gliosarcoma metabolism, Humans, Immunohistochemistry methods, Magnetic Resonance Imaging, Male, Neoplasm Recurrence, Local, Aphasia etiology, Brain Neoplasms diagnosis, Gliosarcoma diagnosis, Headache etiology
- Abstract
A 28-year-old man presented with a short history of headache, visual and aphasic speech disturbances. MR scans revealed a large, partly cystic, contrast-enhancing lesion of the left temporal lobe that upon microscopic examination was diagnosed as pleomorphic xanthoastrocytoma (PXA) with anaplastic features (WHO grade III). Remarkably, this tumor featured an unusual gliovascular, rosette-like histoarchitecture, which had previously been hypothesized to possibly indicate a greater likelihood of PXA recurrence. Indeed, only 14 months later, the patient presented with a recurrent lesion, which contained the previous histology, but now also featured a distinct fibrosarcoma-like component replete with numerous osteoclast-type giant cells. In addition, whereas eosinophilic granular bodies were plentiful at the lesion's periphery, numerous CD34 - positive satellite cells were found in the adjacent non-infiltrated cortex. Regarding the origin of this recurrent tumor and in reflection of its composition of distinct PXA as well as sarcomatous components, the diagnosis of a pleomorphic xanthoastrosarcoma, to be conceptually considered as a gliosarcoma subtype, was made.To our knowledge, this is an unprecedented case of sarcomatous transformation of a PXA. Particular attention should be given to gliovascular pseudopapillary structures in PXAs, the presence of which may potentially herald a more aggressive clinical behavior.
- Published
- 2009
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- View/download PDF
183. GABA receptor subunits in human auditory cortex in normal and stroke cases.
- Author
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Sacco CB, Tardif E, Genoud C, Probst A, Tolnay M, Janzer RC, Verney C, Kraftsik R, and Clarke S
- Subjects
- Adult, Aged, Aged, 80 and over, Auditory Cortex pathology, Auditory Cortex ultrastructure, Female, Humans, Male, Microscopy, Electron, Transmission methods, Microscopy, Immunoelectron, Middle Aged, Postmortem Changes, Auditory Cortex metabolism, Down-Regulation physiology, Protein Subunits metabolism, Receptors, GABA-A metabolism, Stroke pathology
- Abstract
GABA receptors are ubiquitous in the cerebral cortex and play a major role in shaping responses of cortical neurons. GABA(A) and GABA(B) receptor subunit expression was visualized by immunohistochemistry in human auditory areas from both hemispheres in 9 normal subjects (aged 43-85 years; time between death and fixation 6-24 hours) and in 4 stroke patients (aged 59-87 years; time between death and fixation 7-24 hours) and analyzed qualitatively for GABA(A) and semiquantitatively for GABA(B) receptor subunits. In normal brains, the primary auditory area (TC) and the surrounding areas TB and TA displayed distinct GABA(A) receptor subunit labeling with differences among cortical layers and areas. In postacute and chronic stroke we found a layer-selective downregulation of the alpha-2 subunit in the anatomically intact cerebral cortex of the intact and of the lesioned hemisphere, whereas the alpha-1, alpha-3 and beta-2/3 subunits maintained normal levels of expression. The GABA(B) receptors had a distinct laminar pattern in auditory areas and minor differences among areas. Unlike in other pathologies, there is no modulation of the GABA(B) receptor expression in subacute or chronic stroke.
- Published
- 2009
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- View/download PDF
184. Lentivirus Tau (P301S) expression in adult amyloid precursor protein (APP)-transgenic mice leads to tangle formation.
- Author
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Osinde M, Clavaguera F, May-Nass R, Tolnay M, and Dev KK
- Subjects
- Amyloid beta-Protein Precursor metabolism, Animals, Blotting, Western, CHO Cells, Cricetinae, Cricetulus, Genetic Vectors, Hippocampus metabolism, Lentivirus, Mice, Mice, Transgenic, Neurofibrillary Tangles genetics, Neurofibrillary Tangles metabolism, tau Proteins genetics, Amyloid beta-Protein Precursor genetics, Hippocampus pathology, Neurofibrillary Tangles pathology, tau Proteins metabolism
- Abstract
Aims: In this study, we aimed to investigate the interaction between amyloid- and Tau-associated pathologies to gain further insights into the development of Alzheimer's disease. We examined the formation of neurofibrillary tangles (NFT) in adult mouse brain without the prior overexpression of Tau at embryonic or early post-natal stages to dissociate any developmental mechanisms., Methods: Lentivirus technology was used to examine the effects of overexpressing mutant Tau-P301S in the adult mouse brains of both wild-type and amyloid precursor protein (APP)-transgenic mice., Results: We find that injection of lentivirus Tau-P301S into the hippocampus of adult wild-type mice increases levels of hyperphosphorylated Tau, as early as 3 months post injection. However, no NFT are found even after 13 months of Tau expression. In contrast, the overexpression of Tau-P301S in adult APP-transgenic animals results in the formation of Gallyas-stained NFT., Conclusions: Our current findings are the first to show that overexpression of Tau-P301S in adult mice overexpressing APP, but not wild-type mice, leads to enhanced Tau-related pathology.
- Published
- 2008
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- View/download PDF
185. Allograft inflammatory factor-1: a pathogenetic factor for vasculitic neuropathy.
- Author
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Broglio L, Erne B, Tolnay M, Schaeren-Wiemers N, Fuhr P, Steck AJ, and Renaud S
- Subjects
- Adult, Aged, Arteries metabolism, Arteries pathology, Arteries physiopathology, Biomarkers analysis, Biomarkers metabolism, Biopsy, Calcium-Binding Proteins, Chemotaxis, Leukocyte immunology, DNA-Binding Proteins analysis, Female, Humans, Immunohistochemistry, Male, Microfilament Proteins, Middle Aged, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, Muscle, Smooth, Vascular physiopathology, Peripheral Nerves pathology, Peripheral Nerves physiopathology, Peripheral Nervous System Diseases pathology, Peripheral Nervous System Diseases physiopathology, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating pathology, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating physiopathology, Sural Nerve metabolism, Sural Nerve pathology, Sural Nerve physiopathology, Up-Regulation physiology, Vasculitis pathology, Vasculitis physiopathology, DNA-Binding Proteins metabolism, Peripheral Nerves metabolism, Peripheral Nervous System Diseases metabolism, Polyradiculoneuropathy, Chronic Inflammatory Demyelinating metabolism, Vasculitis metabolism
- Abstract
Allograft inflammatory factor-1 (AIF-1) is a cytokine that plays a major role in the immune response and proliferative vasculopathy that occur during chronic allograft rejection. The purpose of this study was to characterize the cellular expression pattern and pathogenetic role of AIF-1 in nerve biopsies from patients with vasculitic neuropathy. We performed immunohistochemistry in human nerve biopsies of 10 patients with vasculitic neuropathies (VASs), 6 with chronic inflammatory demyelinating polyneuropathies (CIDPs), 5 with noninflammatory axonal neuropathies (NIANs), and 3 control nerves (CNs). In the CIDP and VAS nerves, AIF-1 expression was higher than in CN and NIAN nerves (P < 0.05). AIF-1 was increased in the arterial walls of VAS compared with CIDP nerves (P < 0.05). Vascular smooth muscle cells in vasculitic nerve express AIF-1 at a higher level compared with CIDP and NIAN. AIF-1 plays a role in inflammatory nerve disease and vascular smooth muscle cell proliferation and may be a new molecular target for treatment.
- Published
- 2008
- Full Text
- View/download PDF
186. Considerations for the development of therapeutic monoclonal antibodies.
- Author
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Swann PG, Tolnay M, Muthukkumar S, Shapiro MA, Rellahan BL, and Clouse KA
- Subjects
- Animals, Antibodies, Monoclonal adverse effects, Cytokines metabolism, Humans, Immunoglobulin Fc Fragments therapeutic use, Immunoglobulin Isotypes therapeutic use, Protein Engineering, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Immunoglobulin Fc Fragments immunology, Immunoglobulin Isotypes immunology
- Abstract
An increasing number of Investigational New Drug (IND) applications for therapeutic monoclonal antibodies (mAbs) have been submitted to US FDA over the past several years. Monoclonal antibodies and related products are under development for a wide range of indications. In addition, the diversity of antibody-related products is increasing including IgG2/IgG4 subclasses and engineered Fc regions to enhance or reduce antibody effector functionality. Recent findings highlight the need to more fully characterize these products and their activity. Advances in product characterization tools, immunogenicity assessments, and other bioanalytical assays can be used to better understand product performance and facilitate development.
- Published
- 2008
- Full Text
- View/download PDF
187. MAPT S305I mutation: implications for argyrophilic grain disease.
- Author
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Kovacs GG, Pittman A, Revesz T, Luk C, Lees A, Kiss E, Tariska P, Laszlo L, Molnár K, Molnar MJ, Tolnay M, and de Silva R
- Subjects
- Adult, Humans, Immunohistochemistry, Magnetic Resonance Imaging, Male, Microscopy, Confocal, Microscopy, Electron, Transmission, Mutation, Reverse Transcriptase Polymerase Chain Reaction, tau Proteins analysis, tau Proteins metabolism, Brain pathology, Dementia genetics, Dementia pathology, tau Proteins genetics
- Abstract
Frontotemporal lobar degeneration (FTLD) with mutations in the tau gene (MAPT) causes familial frontotemporal dementia with tau pathology. Many of these mutations result in morphological phenotypes resembling sporadic tauopathies, although, to date, no such cases mimicking argyrophilic grain disease (AgD) have been documented. We now present a case with a novel S305I MAPT mutation and a morphological phenotype showing resemblance to AgD. At the age of 39, the patient developed behavioural and personality changes and lack of verbal fluency with later poor performance on naming tasks and rigidity in the extremities. After a short disease course of 1.5 years, the patient died. A unique neuropathological phenotype with neuronal diffuse cytoplasmic tau immunoreactivity, oligodendroglial-coiled bodies, argyrophilic grains, and non-argyrophilic, but tau-immunopositive and ubiquitin-immunonegative pre-grains were observed, whereas classical neurofibrillary tangles, Pick bodies, and neuritic plaques were absent. The tau-positive abnormal structures were composed only of 4R-tau isoforms and, ultrastructurally, straight filaments. Neuronal loss was greatest in the medial temporal cortex, hippocampus, and amygdala. These pathological features resemble AgD. The novel S305I substitution has a strong effect on MAPT exon 10 splicing, thereby causing a striking increase in 4R-tau isoforms. Our observation not only widens the phenotypic spectrum of FTLD with MAPT mutation but also underpins the notion that the predominance of similar neuropathological findings in sporadic AgD cases may be viewed as features of a distinct disease entity.
- Published
- 2008
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188. [Primary cerebellar T-cell lymphoma].
- Author
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Zimpfer A, Wasner M, Fend F, Tolnay M, and Dirnhofer S
- Subjects
- Cerebellar Neoplasms drug therapy, Fatal Outcome, Gene Rearrangement, T-Lymphocyte, Humans, Lymphoma, T-Cell drug therapy, Male, Methotrexate therapeutic use, Middle Aged, Molecular Biology, Cerebellar Neoplasms pathology, Lymphoma, T-Cell pathology, Pneumocystis Infections pathology, Receptors, Antigen, T-Cell genetics
- Abstract
Primary central nervous system T-cell lymphomas are rare and have to be differentiated from reactive lesions. It is therefore essential to use all possible tools to establish the diagnosis, including immunohistochemistry, molecular genetic analysis, and/or cytogenetic methods. In this paper we present the case of a primary cerebellar T-cell lymphoma in a 50-year-old man; a clonal T-cell receptor gene rearrangement was documented. After two cycles of methotrexate therapy the patient developed Pneumocystis carinii-induced pneumonia, dying 10 weeks after his diagnosis. The autopsy did not reveal any residual tumour.
- Published
- 2008
- Full Text
- View/download PDF
189. Clinical course of neuropathologically confirmed frontal-variant Alzheimer's disease.
- Author
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Taylor KI, Probst A, Miserez AR, Monsch AU, and Tolnay M
- Subjects
- Aged, Alzheimer Disease diagnosis, Behavioral Symptoms diagnosis, Behavioral Symptoms pathology, Behavioral Symptoms psychology, Cognition Disorders diagnosis, Cognition Disorders pathology, Cognition Disorders psychology, Humans, Male, Personality Disorders diagnosis, Personality Disorders pathology, Personality Disorders psychology, Alzheimer Disease pathology, Alzheimer Disease psychology, Frontal Lobe pathology
- Abstract
Background A 66-year-old man presented with a 3-year history of personality changes marked by increasing apathy, social withdrawal and deficits in complex attention, and a 1-year history of progressive memory problems and difficulties in planning and carrying out complex tasks. Investigations Three neuropsychological examinations over 2 years, neurological examination, routine laboratory tests, brain MRI, single-photon emission CT scan, genetic analyses, and neuropathological examination. Diagnosis A clinical diagnosis of frontal-variant frontotemporal dementia was superseded by postmortem neuropathological evidence, which established a diagnosis of frontal-variant Alzheimer's disease. Management The patient and his spouse were referred for counseling, and the patient was referred for follow-up examinations.
- Published
- 2008
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190. New insights into the pathology of Parkinson's disease: does the peripheral autonomic system become central?
- Author
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Probst A, Bloch A, and Tolnay M
- Subjects
- Autonomic Nervous System chemistry, Autonomic Nervous System Diseases etiology, Autonomic Nervous System Diseases pathology, Central Nervous System chemistry, Humans, Lewy Bodies pathology, Parkinson Disease etiology, alpha-Synuclein analysis, Autonomic Nervous System pathology, Central Nervous System pathology, Parkinson Disease pathology
- Abstract
Recent studies in aged, neurologically unimpaired subjects have pointed to a specific induction site of the pathological process of Parkinson's disease (PD) in the region of the dorsal glossopharyngeus-vagus complex as well as in the anterior olfactory nucleus. From the lower brainstem, the disease process would then pursue an ascending course and involve more rostral brainstem areas, limbic structures, and eventually the cerebral cortex. One barrier to the acceptance of the caudal medullary structures as the induction site of PD pathology is that not all parts of the nervous system have been investigated for the presence of PD-associated lesions in cases of early asymptomatic PD. Using alpha-synuclein immunostaining, we investigated the brain, the sacral, and thoracic autonomic nuclei of the spinal cord as well as several components of the peripheral autonomic nervous system in a autopsy cohort of 98 neurologically unimpaired subjects aged 64 or more. Our data indicate that the autonomic nuclei of the spinal cord and the peripheral autonomic nervous system belong to the most constantly and earliest affected regions next to medullary structures and the olfactory nerves in neurologically unimpaired older individuals, thus providing a pathological basis for early premotor autonomic dysfunctions at a prodromal stage of PD.
- Published
- 2008
- Full Text
- View/download PDF
191. Assessment of nerve damage using a novel ultrasonic device for bone cutting.
- Author
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Schaeren S, Jaquiéry C, Heberer M, Tolnay M, Vercellotti T, and Martin I
- Subjects
- Animals, Foot innervation, Foot physiopathology, Male, Osteotomy adverse effects, Rats, Recovery of Function physiology, Time Factors, Osteotomy instrumentation, Sciatic Nerve injuries, Ultrasonic Therapy instrumentation
- Published
- 2008
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192. The validity of clinical diagnoses of dementia in a group of consecutively autopsied memory clinic patients.
- Author
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Gay BE, Taylor KI, Hohl U, Tolnay M, and Staehelin HB
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease diagnosis, Alzheimer Disease mortality, Alzheimer Disease pathology, Dementia mortality, Dementia, Vascular diagnosis, Dementia, Vascular mortality, Dementia, Vascular pathology, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Prevalence, Reproducibility of Results, Sensitivity and Specificity, Severity of Illness Index, Biopsy standards, Dementia diagnosis, Dementia pathology
- Abstract
Background: Epidemiological studies show that up to 10% of individuals aged 65 years and older suffer from dementia, most commonly from dementia of the Alzheimer Type (DAT) (1). Clinicopathological studies are critical to our understanding of this disease and improving the accuracy of clinical diagnoses., Objectives: Our objectives were to examine the validity of clinical diagnoses of DAT, to determine the prevalence of different forms of dementia in this sample, and to investigate the relationship between age at death and polymorbidity., Subjects and Method: Clinical data were available from 221 patients who had been examined at the Basel Memory Clinic between 1986 and 1996. From this population, 34% (75 patients) were autopsied in the Department of Pathology, University Hospital Basel, and neuropathological examinations were additionally performed on 62 (83%) of these patients. Clinical and neuropathological data were retrospectively compared., Results: 67.8% of the neuropathologically examined patients received a definitive diagnosis of AD (Alzheimer's disease), vascular dementia (VaD) or mixed dementia (AD and VaD). AD alone or with other histopathological hallmarks of dementia was the most prevalent neuropathological diagnosis (63%). VaD was deemed the only cause of dementia in only 4.8% of patients. The sensitivity for DAT was 75.9%, the specificity 60.6%. Increasing age was associated with an increasing number of clinical and neuropathological diagnoses., Conclusion: The sensitivity and specificity of the clinical diagnoses of DAT found in our study are similar to previous reports (2-5). Older patients had more etiologies of their dementia than younger patients. This study reaffirms the need for internationally accepted criteria for clinical and neuropathological diagnoses, as well as further clinical-neuropathological investigations to further refine the clinical diagnostic process.
- Published
- 2008
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193. Bilateral vertebral giant cell arteritis--favourable outcome in two cases.
- Author
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Sutter R, Renaud S, Bonati L, Lyrer P, Tolnay M, Wetzel S, Rüegg S, and Engelter S
- Subjects
- Aged, Aged, 80 and over, Brain Stem blood supply, Brain Stem pathology, Brain Stem physiopathology, Cerebellum blood supply, Cerebellum pathology, Cerebellum physiopathology, Dose-Response Relationship, Drug, Female, Giant Cell Arteritis drug therapy, Humans, Immunosuppressive Agents administration & dosage, Magnetic Resonance Imaging, Male, Methylprednisolone administration & dosage, Treatment Outcome, Ultrasonography, Vertebral Artery diagnostic imaging, Vertebral Artery pathology, Vertebrobasilar Insufficiency drug therapy, Giant Cell Arteritis physiopathology, Vertebral Artery physiopathology, Vertebrobasilar Insufficiency etiology, Vertebrobasilar Insufficiency physiopathology
- Published
- 2008
- Full Text
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194. Hereditary systemic angiopathy (HSA) with cerebral calcifications, retinopathy, progressive nephropathy, and hepatopathy.
- Author
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Winkler DT, Lyrer P, Probst A, Devys D, Haufschild T, Haller S, Willi N, Mihatsch MJ, Steck AJ, and Tolnay M
- Subjects
- Adult, Aged, Brain blood supply, Brain pathology, Brain physiopathology, Calcinosis pathology, Calcinosis physiopathology, Cerebral Arterial Diseases physiopathology, Cerebral Arteries pathology, Cerebral Arteries physiopathology, Disease Progression, Early Diagnosis, Female, Humans, Immunosuppressive Agents therapeutic use, Kidney Diseases physiopathology, Liver Diseases physiopathology, Liver Failure pathology, Liver Failure physiopathology, Male, Microcirculation pathology, Microcirculation physiopathology, Middle Aged, Renal Insufficiency pathology, Renal Insufficiency physiopathology, Retinal Artery pathology, Retinal Artery physiopathology, Retinal Diseases physiopathology, Syndrome, Treatment Outcome, Vascular Diseases physiopathology, Vasculitis pathology, Vasculitis physiopathology, Viscera blood supply, Viscera pathology, Viscera physiopathology, Cerebral Arterial Diseases pathology, Kidney Diseases pathology, Liver Diseases pathology, Retinal Diseases pathology, Vascular Diseases pathology
- Abstract
Several hereditary conditions affecting cerebral, retinal and systemic microvessels have recently been described. They include CADASIL, CRV, and HERNS. We here report on a variant form of a hereditary systemic angiopathy (HSA) affecting two generations of a Caucasian family. Clinical symptoms of HSA appear in the mid-forties and are characterized by visual impairment, migraine-like headache, skin rash, epileptic seizures, progressive motor paresis and cognitive decline. Late symptoms include hepatic and renal failure. Retinal capillary microaneurysms and arteriolar tortuosity are associated with marked optic disc atrophy. Radiological hallmarks consist of multiple cerebral calcifications and tumor-like subcortical white matter lesions. Brain, peripheral nerve, muscle, kidney and colon biopsies have revealed a multi organ small vessel involvement with partly altered endothelium, perivascular inflammation and thrombotic microangiopathy. No curative therapeutic options are known for hereditary cerebral vasculopathies. The use of cyclophosphamide, azathioprine and methotrexate was of no benefit in our cases of HSA. Early diagnosis of hereditary systemic angiopathies is important in order to prevent patients from repetitive invasive diagnostic measures and to avoid the use of inappropriate and potentially harmful drugs.
- Published
- 2008
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195. Argyrophilic grain disease.
- Author
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Tolnay M and Probst A
- Subjects
- Brain ultrastructure, Dementia epidemiology, Dementia genetics, Humans, Neurodegenerative Diseases epidemiology, Neurodegenerative Diseases genetics, Brain pathology, Dementia complications, Dementia pathology, Neurodegenerative Diseases complications, Neurodegenerative Diseases pathology
- Published
- 2008
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196. Tauopathy models and human neuropathology: similarities and differences.
- Author
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Frank S, Clavaguera F, and Tolnay M
- Subjects
- Animals, Humans, Mice, Mice, Transgenic, Disease Models, Animal, Tauopathies pathology, Tauopathies physiopathology
- Abstract
Much of our current understanding of the pathogenic mechanisms in human neurodegenerative disorders has been derived from animal studies. As such, transgenic mouse models have significantly contributed to the development of novel pathogenic concepts underlying human tauopathies, a group of diseases comprising various forms of neurodegenerative disorders including Alzheimer's disease, corticobasal degeneration, argyrophilic grain disease, progressive supranuclear palsy, and Pick's disease as well as hereditary fronto-temporal dementia with parkinsonism linked to chromosome 17. Here, we will review in vivo models of human tauopathies with particular preference to transgenic mouse models. Strengths and limitations of these models in recapitulating the complex pathogenesis of tauopathies will be discussed.
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- 2008
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197. Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice.
- Author
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Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, Lewis J, Hutton M, Tolnay M, and Jucker M
- Subjects
- Alzheimer Disease metabolism, Amyloid beta-Peptides administration & dosage, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor administration & dosage, Amyloid beta-Protein Precursor metabolism, Animals, Brain Chemistry, Cell Extracts administration & dosage, Cell Extracts toxicity, Female, Mice, Mice, Transgenic, Tauopathies metabolism, tau Proteins genetics, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides toxicity, Amyloid beta-Protein Precursor toxicity, Tauopathies genetics, Tauopathies pathology
- Abstract
Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-beta (A beta) deposits, and neurofibrillary lesions, which consist of intracellular aggregates of hyperphosphorylated tau protein. To study the in vivo induction of tau pathology, dilute brain extracts from aged A beta-depositing APP23 transgenic mice were intracerebrally infused in young B6/P301L tau transgenic mice. Six months after the infusion, tau pathology was induced in the injected hippocampus but also in brain regions well beyond the injection sites such as the entorhinal cortex and amygdala, areas with neuronal projection to the injection site. No or only modest tau induction was observed when brain extracts from aged nontransgenic control mice and aged tau-depositing B6/P301L transgenic mice were infused. To further study A beta-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although A beta deposition in double-transgenic mice did not differ from single APP23 transgenic mice, double-transgenic mice revealed increased tau pathology compared to single B6/P301L tau transgenic mice predominately in areas with high A beta plaque load. The present results suggest that both extract-derived A beta species and deposited fibrillary A beta can induce the formation of tau neurofibrillary pathology. The observation that infused A beta can trigger the tau pathology in the absence of A beta deposits provides an explanation for the discrepancy between the neuroanatomical location of A beta deposits and the development and spreading of tau lesions in Alzheimer's disease brain.
- Published
- 2007
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198. Elf-1 binds to GGAA elements on the FcRgamma promoter and represses its expression.
- Author
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Juang YT, Sumibcay L, Tolnay M, Wang Y, Kyttaris VC, and Tsokos GC
- Subjects
- Base Sequence, Binding Sites, Cell Line, Humans, Protein Binding, Down-Regulation, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins c-ets metabolism, Receptors, IgG genetics, Transcription Factors metabolism
- Abstract
The Fc receptor (FcR) gamma-chain has been shown to be up-regulated in T cells when the TCR zeta-chain is decreased. We demonstrate that Elf-1, but not other Ets family transcription factors, bind to a cluster of GGAA sites located within the 200 bp upstream from the transcription initiation site of the FcRgamma promoter. Forced expression of Elf-1 results in the suppression of FcRgamma expression, whereas silencing its expression with small interfering RNA Elf-1 results in increased FcRgamma expression. Elf-1 represents the first transcription factor identified to be involved in the transcriptional regulation of FcRgamma, and cells that fail to express Elf-1, as is the case with human systemic lupus erythematosus T cells, will express FcRgamma-chain.
- Published
- 2007
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199. Hippocampal sclerosis dementia: a reappraisal.
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Probst A, Taylor KI, and Tolnay M
- Subjects
- Humans, Nerve Degeneration pathology, Sclerosis, Dementia pathology, Hippocampus pathology
- Abstract
Hippocampal sclerosis (HpScl) is characterized by neuronal loss and gliosis in CA1 and subiculum of the hippocampus, and may be one contributing factor to dementia in old age. The term hippocampal sclerosis dementia (HpSclD) designates the presence of both hippocampal sclerotic lesions and a dementia syndrome. In the present review, we outline the pathological heterogeneity underlying HpSclD and discuss related disorders due to tau protein pathology and frontotemporal dementia with ubiquitin positive inclusions (FTLD-U). We also provide a detailed morphological description of ten of our own autopsied HpSclD cases, and compare these pathological findings with those reported in the literature. The lateralization of HpScl and the atrophy of the mammillary bodies were striking features in most of our cases. The main pathology consisted of tau positive lesions with a predominance of neuronal and glial pretangles in Ammon's horn and the dentate gyrus. Neurofibrillary and ghost tangles in CA1 and the subiculum were scarce and thus insufficient to explain the hippocampal pyramidal cell loss. In some cases, tau pathology in the hippocampal formation coexisted with glial tau pathology in the frontal cortex. The most striking finding besides the tau pathology was the presence of concomitant neuronal cytoplasmic inclusions and neurites immunoreactive for the transactive response DNA-binding protein-43 (TDP-43) in the dentate gyrus and temporal neocortex, similar to those found in FTLD-U. Taken together, the pathology of HpSclD is indicative of a degenerative rather than a hypoxic/ischemic etiology of HpSclD. Presently, HpSclD may best be deemed a disorder with various neurodegenerative etiologies, most notably tauopathy and TDP-43 proteinopathy (i.e. FTLD-U). Each of these disease processes could either independently or concertedly account for the dementia syndrome in HpSclD.
- Published
- 2007
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200. [Meningothelial meningioma in a mature cystic teratoma of the ovary].
- Author
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Adams H, Went P, Tolnay M, Sartorius G, and Singer G
- Subjects
- Adult, Desmoplakins metabolism, Female, Humans, Immunohistochemistry, Meningeal Neoplasms complications, Meningeal Neoplasms diagnostic imaging, Meningioma complications, Meningioma diagnostic imaging, Mucin-1 metabolism, Ultrasonography, Meningeal Neoplasms pathology, Meningioma pathology, Ovarian Neoplasms pathology, Teratoma pathology
- Abstract
Mature teratomas belong to the group of germ cell tumors of the ovary. They account for 27-44% of all ovarian neoplasms and up to 58% of all benign tumors of the ovary. In mature as well as in immature teratomas, secondary tumors originating from the three embryonic tissue components may be found. These tumors can show benign or malignant behavior. We report the case of a meningothelial meningioma, found within a mature teratoma of a 32 year old female. The characteristic histomorphology and immunohistochemical expression for epithelial membrane antigen (EMA) and desmoplakin are diagnostic.
- Published
- 2007
- Full Text
- View/download PDF
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