T Arendt

University of Leipzig, Leipzig, Saxony, Germany

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Publications (330)1096.75 Total impact

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    ABSTRACT: Neurodegeneration in Alzheimer's disease (AD) is characterized by pathological protein aggregates and inadequate activation of cell cycle regulating proteins. Recently, Smad proteins were identified to control the expression of AD relevant proteins such as APP, CDK4 and CDK inhibitors, both critical regulators of cell cycle activation. This might indicate a central role for Smads in AD pathology where they show a substantial deficiency and disturbed subcellular distribution in neurons. Still, the mechanisms driving relocation and decrease of neuronal Smad in AD are not well understood. However, Pin1, a peptidyl-prolyl-cis/trans-isomerase, which allows isomerization of tau protein, was recently identified also controlling the fate of Smads. Here we analyse a possible role of Pin1 for Smad disturbances in AD.
    Neuropathology and Applied Neurobiology 06/2014; · 4.84 Impact Factor
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    ABSTRACT: Tau is the major microtubule-associated protein in neurons involved in microtubule stabilization in the axonal compartment. Changes in tau gene expression, alternative splicing and posttranslational modification regulate tau function and in tauopathies can result in tau mislocalization and dysfunction, causing tau aggregation and cell death. To uncover proteins involved in the development of tauopathies, a yeast two-hybrid system was used to screen for tau-interacting proteins. We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We defined the tau binding domain to amino acids 552-682 of axotrophin comprising the RING-variant domain. Co-immunoprecipitation and co-localization confirmed the specificity of the interaction. Intracellular localization of axotrophin is determined by an N-terminal nuclear targeting signal and a C-terminal nuclear export signal. In AD brain nuclear localization is lost and axotrophin is rather associated with neurofibrillary tangles. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. In vitro ubiquitination of four-repeat tau results in incorporation of up to four ubiquitin molecules compared to two molecules in three-repeat tau. In summary, we present a novel tau modification occurring preferentially on 4-repeat tau protein which modifies microtubule-binding and may impact on the pathogenesis of tauopathies.
    Biochimica et biophysica acta. 06/2014;
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    ABSTRACT: Gliosis of retinal Müller glial cells may have both beneficial and detrimental effects on neurons. To investigate the role of purinergic signaling in ischemia-induced reactive gliosis, transient retinal ischemia was evoked by elevation of the intraocular pressure in wild-type (Wt) mice and in mice deficient in the glia-specific nucleotide receptor P2Y1 (P2Y1 receptor-deficient (P2Y1R-KO)). While control retinae of P2Y1R-KO mice displayed reduced cell numbers in the ganglion cell and inner nuclear layers, ischemia induced apoptotic death of cells in all retinal layers in both, Wt and P2Y1R-KO mice, but the damage especially on photoreceptors was more pronounced in retinae of P2Y1R-KO mice. In contrast, gene expression profiling and histological data suggest an increased survival of amacrine cells in the postischemic retina of P2Y1R-KO mice. Interestingly, measuring the ischemia-induced downregulation of inwardly rectifying potassium channel (Kir)-mediated K(+) currents as an indicator, reactive Müller cell gliosis was found to be weaker in P2Y1R-KO (current amplitude decreased by 18%) than in Wt mice (decrease by 68%). The inner retina harbors those neurons generating action potentials, which strongly rely on an intact ion homeostasis. This may explain why especially these cells appear to benefit from the preserved Kir4.1 expression in Müller cells, which should allow them to keep up their function in the context of spatial buffering of potassium. Especially under ischemic conditions, maintenance of this Müller cell function may dampen cytotoxic neuronal hyperexcitation and subsequent neuronal cell loss. In sum, we found that purinergic signaling modulates the gliotic activation pattern of Müller glia and lack of P2Y1 has janus-faced effects. In the end, the differential effects of a disrupted P2Y1 signaling onto neuronal survival in the ischemic retina call the putative therapeutical use of P2Y1-antagonists into question.
    Cell Death & Disease 01/2014; 5:e1353. · 6.04 Impact Factor
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    ABSTRACT: Tau is the major microtubule-associated protein in neurons involved in microtubule stabilization in the axonal compartment. Changes in tau gene expression, alternative splicing and posttranslational modification regulate tau function and in tauopathies can result in tau mislocalization and dysfunction, causing tau aggregation and cell death. To uncover proteins involved in the development of tauopathies, a yeast two-hybrid system was used to screen for tau-interacting proteins. We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We defined the tau binding domain to amino acids 552-682 of axotrophin comprising the RING-variant domain. Co-immunoprecipitation and co-localization confirmed the specificity of the interaction. Intracellular localization of axotrophin is determined by an N-terminal nuclear targeting signal and a C-terminal nuclear export signal. In AD brain nuclear localization is lost and axotrophin is rather associated with neurofibrillary tangles. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. In vitro ubiquitination of four-repeat tau results in incorporation of up to four ubiquitin molecules compared to two molecules in three-repeat tau. In summary, we present a novel tau modification occurring preferentially on 4-repeat tau protein which modifies microtubule-binding and may impact on the pathogenesis of tauopathies.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 01/2014; · 4.91 Impact Factor
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    ABSTRACT: In Alzheimer's disease (AD), different types of neurons and different brain areas show differential patterns of vulnerability towards neurofibrillary degeneration, which provides the basis for a highly predictive profile of disease progression throughout the brain that now is widely accepted for neuropathological staging. In previous studies we could demonstrate that in AD cortical and subcortical neurons are constantly less frequently affected by neurofibrillary degeneration if they are enwrapped by a specialized form of the hyaluronan-based extracellular matrix (ECM), the so called 'perineuronal net' (PN). PNs are basically composed of large aggregating chondroitin sulphate proteoglycans connected to a hyaluronan backbone, stabilized by link proteins and cross-linked via tenascin-R (TN-R). Under experimental conditions in mice, PN-ensheathed neurons are better protected against iron-induced neurodegeneration than neurons without PN. Still, it remains unclear whether these neuroprotective effects are directly mediated by the PNs or are associated with some other mechanism in these neurons unrelated to PNs. To identify molecular components that essentially mediate the neuroprotective aspect on PN-ensheathed neurons, we comparatively analysed neuronal degeneration induced by a single injection of FeCl3 on four different mice knockout strains, each being deficient for a different component of PNs. Aggrecan, link protein and TN-R were identified to be essential for the neuroprotective properties of PN, whereas the contribution of brevican was negligible. Our findings indicate that the protection of PN-ensheathed neurons is directly mediated by the net structure and that both the high negative charge and the correct interaction of net components are essential for their neuroprotective function.
    Cell Death & Disease 01/2014; 5:e1119. · 6.04 Impact Factor
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    ABSTRACT: This study stresses the hypothesis whether hypoxic events contribute to formation and deposition of β-amyloid (Aβ) in cerebral blood vessels by affecting the processing of endothelial amyloid precursor protein (APP). Therefore, cerebral endothelial cells (ECs) derived from transgenic Tg2576 mouse brain, were subjected to short periods of hypoxic stress, followed by assessment of formation and secretion of APP cleavage products sAPPα, sAPPβ, and Aβ as well as the expression of endothelial APP. Hypoxic stress of EC leads to enhanced secretion of sAPPβ into the culture medium as compared to normoxic controls, which is accompanied by increased APP expression, induction of vascular endothelial growth factor (VEGF) synthesis, nitric oxide production, and differential changes in endothelial p42/44 (ERK1/2) expression. The hypoxia-mediated up-regulation of p42/44 at a particular time of incubation was accompanied by a corresponding down-regulation of the phosphorylated form of p42/44. To reveal any role of hypoxia-induced VEGF in endothelial APP processing, ECs were exposed by VEGF. VEGF hardly affected the amount of sAPPβ and Aβ(1-40) secreted into the culture medium, whereas the suppression of the VEGF receptor action by SU-5416 resulted in decreased release of sAPPβ and Aβ(1-40) in comparison to control incubations, suggesting a role of VEGF in controlling the activity of γ-secretase, presumably via the VEGF receptor-associated tyrosine kinase. The data suggest that hypoxic stress represents a mayor risk factor in causing Aβ deposition in the brain vascular system by favoring the amyloidogenic route of endothelial APP processing. The hypoxic-stress-induced changes in β-secretase activity are presumably mediated by altering the phosphorylation status of p42/44, whereas the stress-induced up-regulation of VEGF appears to play a counteracting role by maintaining the balance of physiological APP processing.
    Nutritional Neuroscience 11/2013; · 1.65 Impact Factor
  • Neurobiology of aging 11/2013; · 5.94 Impact Factor
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    ABSTRACT: Brains of Alzheimer's disease (AD) patients are characterized in part by the formation of high molecular weight aggregates of amyloid-β (Aβ) peptides, which interfere with neuronal function and provoke neuronal cell death. The pyroglutamate (pGlu) modification of Aβ was demonstrated to be catalyzed by the enzyme glutaminyl cyclase (QC) and to enhance pathogenicity and neurotoxicity. Here, we addressed the role of QC in AD pathogenesis in human cortex. Two sets of human postmortem brain tissue from a total of 13 non-demented controls and 11 AD cases were analyzed by immunohistochemistry and unbiased stereology, quantitative RT-PCR, and enzymatic activity assays for the expression level of QC in temporal and entorhinal cortex. Additionally, cortical Aβ and pGlu-Aβ concentrations were quantified by ELISA. Data on QC expression and Aβ peptide concentrations were correlated with each other and with the Mini-Mental State Examination (MMSE) of individual cases. In control cases, QC expression was higher in the more vulnerable entorhinal cortex than in temporal cortex. In AD brains, QC mRNA expression and the immunoreactivity of QC were increased in both cortical regions and frequently associated with pGlu-Aβ deposits. The analyses of individual cases revealed significant correlations between QC mRNA levels and the concentration of insoluble pGlu-Aβ aggregates, but not of unmodified Aβ peptides. Elevated pGlu-Aβ load showed a better correlation with the decline in MMSE than elevated concentration of unmodified Aβ. Our observations provide evidence for an involvement of QC in AD pathogenesis and cognitive decline by QC-catalyzed pGlu-Aβ formation.
    Journal of Alzheimer's disease: JAD 10/2013; · 4.17 Impact Factor
  • Thomas Arendt, Torsten Bullmann
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    ABSTRACT: The present paper provides an overview on adaptive changes in brain structure and learning abilities during hibernation as a behavioral strategy used by several mammalian species to minimize energy expenditure under current or anticipated inhospitable environmental conditions. One cellular mechanism that contributes to the regulated suppression of metabolism and thermogenesis during hibernation is reversible phosphorylation of enzymes and proteins that limits rates of flux through metabolic pathways. Reversible phosphorylation during hibernation also affects synaptic membrane proteins, a process known to be involved in synaptic plasticity. This mechanism of reversible protein phosphorylation also affects the microtubule-associated protein tau, thereby generating a condition that in the adult human brain is associated with aggregation of tau protein to paired helical filements (PHFs) as observed in Alzheimer's disease. Here, we put forward the concept that phosphorylation of tau is a neuroprotective mechanism to escape NMDA-mediated hyperexcitability of neurons that would otherwise occur during slow gradual cooling of the brain. Phosphorylation of tau and its subsequent targeting to subsynaptic sites might, thus work as a kind of "master switch", regulating NMDA receptor mediated synaptic gain in a wide array of neuronal networks, thereby enabling entry into torpor. If this condition lasts to long, however, it may eventually turn into a pathological trigger driving a cascade of events leading to neurodegeneration as in Alzheimer's disease or other "tauopathies".
    AJP Regulatory Integrative and Comparative Physiology 07/2013; · 3.28 Impact Factor
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    ABSTRACT: Typical hallmarks of Alzheimer's disease (AD) are pathologic deposits in cortical and subcortical regions consisting of self-aggregated proteins such as amyloid-beta (Aβ) or tau. Tissue transglutaminase (tTG) catalyses calcium-dependent cross-linking between proteins (transamidation) resulting in protease-resistant isopeptide bonds. Because of this ability, tTG was suspected to participate in AD pathogenesis. Aβ and tau can be cross-linked by tTG in vitro. In AD neocortex, messenger RNA expression of tTG is increased. However, data on transamidation in AD specimens-activity of not only tTG but also other transglutaminases-are contradictory. The aim of our study was to investigate if tTG is involved in AD development and may be useful as biomarker for AD. We studied human brain samples for tTG concentration, tTG localization, and transamidation activity and cerebrospinal fluid (CSF) for tTG content by novel sensitive and highly specific methods. Neither tTG concentration nor transamidation was increased in AD brain homogenates. Immunohistologically, we found no colocalization of tTG in neocortex sections with tau or Aβ deposits but with blood vessels. Only in rare cases, tTG was detectable in CSF samples. This could be attributed to liberation from erythrocytes. Our data contradict the view that tTG is a potential biochemical marker for AD.
    Neurobiology of aging 06/2013; · 5.94 Impact Factor
  • Sally Hunter, Thomas Arendt, Carol Brayne
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    ABSTRACT: Alzheimer disease (AD) is a progressive, neurodegenerative disease characterised in life by cognitive decline and behavioural symptoms and post-mortem by the neuropathological hallmarks including the microtubule-associated protein tau-reactive tangles and neuritic plaques and amyloid-beta-protein-reactive senile plaques. Greater than 95 % of AD cases are sporadic (SAD) with a late onset and <5 % of AD cases are familial (FAD) with an early onset. FAD is associated with various genetic mutations in the amyloid precursor protein (APP) and the presenilins (PS)1 and PS2. As yet, no disease pathway has been fully accepted and there are no treatments that prevent, stop or reverse the cognitive decline associated with AD. Here, we review and integrate available environmental and genetic evidence associated with all forms of AD. We present the senescence hypothesis of AD progression, suggesting that factors associated with AD can be seen as partial stressors within the matrix of signalling pathways that underlie cell survival and function. Senescence pathways are triggered when stressors exceed the cells ability to compensate for them. The APP proteolytic system has many interactions with pathways involved in programmed senescence and APP proteolysis can both respond to and be driven by senescence-associated signalling. Disease pathways associated with sporadic disease may be different to those involving familial genetic mutations. The interpretation we provide strongly points to senescence as an additional underlying causal process in dementia progression in both SAD and FAD via multiple disease pathways.
    Molecular Neurobiology 04/2013; · 5.47 Impact Factor
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    ABSTRACT: The biochemical properties and subcellular localization of prolyl endopeptidase (PREP) in brain are well characterized and its implications in the realization of cognitive processes and in the pathogenesis of neurodegenerative disorders are a matter of intensive investigation. In contrast, very little is known about its homologue, the PREP-like protein (PREPL). In order to obtain initial hints about the involvement of PREPL in physiological processes, a differential proteomic screen was performed with human skin fibroblasts from controls and patients with PREPL deficiency (hypotonia-cystinuria syndrome). The majority of affected proteins represented cytoskeletal proteins, including caldesmon, tropomyosin α3 chain, lamin A, β-actin, γ-actin, vimentin and zyxin. Therefore, the analysis of PREPL subcellular localization by confocal laser scanning and electron microscopy in mouse neurons was focused on the cytoskeleton. The co-localization of PREPL with cytoskeletal marker proteins such as β-actin and microtubulin-associated protein-2 was observed, in addition to the presence of PREPL within Golgi apparatus and growth cones. In mouse brain, PREPL is neuronally expressed and highly abundant in neocortex, substantia nigra and locus coeruleus. This mirrors to some extent the distribution pattern of PREP and points towards redundant functions of both proteins. In human neocortex, PREPL immunostaining was found in cytoplasm and in neuropil, in particular of layer V pyramidal neurons. This staining was reduced in neocortex of Alzheimer's disease patients. Moreover, in Alzheimer's disease brains, PREPL immunoreactivity was observed in the nucleus and in varicose neuritic processes. Our data indicate physiological functions of PREPL associated with the cytoskeleton, which may be affected under conditions of cytoskeletal degeneration.
    Neuroscience 02/2013; · 3.12 Impact Factor
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    ABSTRACT: Extracellular matrix (ECM) forms an active interface around neurons of the central nervous system (CNS). Whilst the components, chemical heterogeneity and cellular recruitment of this intercellular assembly in various parts of the brain have been discussed in detail, the spinal cord received limited attention in this context. This is in sharp contrast to its clinical relevance since the overall role of ECM especially that of its chondroitin sulphate-based proteoglycan components (CSPGs) was repeatedly addressed in neuropathology, regeneration, CNS repair and therapy models. Based on two post-mortem human specimen, this study gives the first and detailed description of major ECM components of the human spinal cord. Immunohistochemical investigations were restricted to the systematic mapping of aggrecan, brevican, proteoglycan link-protein as well as tenascin-R and hyaluronan containing matrices in the whole cranio-caudal dimension of the human spinal cord. Other proteoglycans like versican, neurocan and NG2 were exemplarily investigated in restricted areas. We show the overall presence of tenascin-R and hyaluronan in both white and grey matters whereas aggrecan, proteoglycan link-protein and brevican were restricted to the grey matter. In the grey matter, the ECM formed aggrecan-based perineuronal nets in the ventral and lateral horns but established single perisynaptic assemblies, axonal coats (ACs), containing link-protein and brevican in all regions except of the Lissauer's zone. Intersegmental differences were reflected in the appearance of segment-specific nuclei but not in overall matrix distribution pattern or chemical heterogeneity. Perineuronal nets were typically associated with long-range projection neurons including cholinergic ventral horn motoneurons or dorsal spinocerebellar tract neurons of the Clarke-Stilling nuclei. Multiple immunolabelling revealed that nociceptive afferents were devoid of individual matrix assemblies unlike glycinergic or GABAergic synapses. The detailed description of ECM distribution in the human spinal cord shall support clinical approaches in injury and regenerative therapy.
    Neuroscience 02/2013; · 3.12 Impact Factor
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    ABSTRACT: The inflammatory response following traumatic brain injury (TBI) contributes to neuronal death with poor outcome. Although anti-inflammatory strategies were beneficial in experimental TBI, clinical translations mostly failed, probably caused by the complexity of involved cells and mediators. We recently showed in a rat model of controlled cortical impact (CCI) that leukotriene inhibitors (LIs) attenuate contusion growth and improve neuronal survival. This study focuses on spatiotemporal characteristics of macrophages and granulocytes, typically involved in inflammatory processes, and neuronal COX-2 expression. Effects of treatment with LIs (Boscari/MK-886), started prior trauma, were evaluated by quantifying CD68(+), CD43(+) and COX-2(+) cells 24h and 72h post-CCI in the parietal cortex (PC), CA3 region, dentate gyrus (DG) and visual/auditory cortex (v/aC). Correlations were applied to identify inter-cellular relationships. At 24h, untreated animals showed granulocyte invasion in all regions, decreasing towards 72h. Macrophages increased from 24h to 72h post-CCI in PC and v/aC. COX-2(+) neurones showed no temporal changes, except of an increase in the CA3 region at 72h. Treatment reduced granulocytes at 24h in the pericontusional zone and hippocampus, and macrophages at 72h in the PC and v/aC. COX-2 expression remained unaffected by LIs, except of time-specific changes in the DG (increase/decrease at 24/72h). Interrelations confirmed concomitant cellular reactions beyond the initial trauma site. In conclusion, LIs attenuated the cellular inflammatory response following CCI. Future studies have to clarify region-specific effects and explore the potential of a clinically more relevant therapeutic approach applying LIs after CCI.
    Brain research 12/2012; · 2.46 Impact Factor
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    ABSTRACT: The microtubule-associated protein tau is mainly expressed in neurons, where it binds and stabilises microtubules. In Alzheimers disease and other tauopathies tau protein has a reduced affinity towards microtubules. As a consequence, tau protein detaches from microtubules and eventually aggregates into β-sheet containing filaments. The fibrillization of monomeric tau to filaments is a multistep process which involves the formation of various aggregates including spherical and protofibrillar oligomers. Previous concepts, primarily developed for Aβ and alpha-synuclein, propose these oligomeric intermediates as the primary cytotoxic species mediating their deleterious effects through membrane permeabilization. In the present study, we, thus, analysed whether this concept can also be applied to tau protein. To this end, viability and membrane integrity were assessed on SH-SY5Y neuroblastoma cells and artificial phospholipid vesicles, treated with tau monomers, tau aggregation intermediates or tau fibrils. Our findings suggest that oligomeric tau aggregation intermediates are the most toxic compounds of tau fibrillogenesis which effectively decrease cell viability and increase phospholipid vesicle leakage. Our data integrate tau protein into the class of amyloidogenic proteins and enforce the hypothesis of a common toxicity-mediating mechanism for amyloidogenic proteins.
    Journal of Biological Chemistry 11/2012; · 4.65 Impact Factor
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    ABSTRACT: The medial nucleus of the trapezoid body (MNTB) is a vital structure of sound localization circuits in the auditory brainstem. Each principal cell of MNTB is contacted by a very large presynaptic glutamatergic terminal, the calyx of Held. The MNTB principal cells themselves are surrounded by extracellular matrix components forming prominent perineuronal nets (PNs). Throughout the CNS, PNs, which form lattice-like structures around the somata and proximal dendrites, are associated with distinct types of neurons. PNs are highly enriched in hyaluronan and chondroitin sulfate proteoglycans therefore providing a charged surface structure surrounding the cell body and proximal neurites of these neurons. The localization and composition of PNs has lead investigators to a number of hypotheses about their functions including: creating a specific extracellular ionic milieu around these neurons, stabilizing synapses, and influencing the outgrowth of axons. However, presently the precise functions of PNs are still quite unclear primarily due to the lack of an ideal experimental model system that is highly enriched in PNs and in which the synaptic transmission properties can be precisely measured. The MNTB principal cells could offer such a model, since they have been extensively characterized electrophysiologically. However, extracellular matrix (ECM) in these neurons has not yet been precisely detailed. The present study gives a detailed examination of the ECM organization and structural differences in PNs of the mouse MNTB. The different PN components and their distribution pattern are scrutinized throughout the MNTB. The data are complemented by electron microscopic investigations of the unique ultrastructural localization of PN-components and their interrelation with distinct pre- and postsynaptic MNTB cell structures. Therefore, we believe this work identifies the MNTB as an ideal system for studying PN function.
    Neuroscience 10/2012; · 3.12 Impact Factor
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    ABSTRACT: Perineuronal matrix is an extracellular protein scaffold to shape neuronal responsiveness and survival. Whilst perineuronal nets engulf the somatodendritic axis of neurons, axonal coats are focal extracellular protein aggregates surrounding individual synapses. Here, we addressed the chemical identity and subcellular localization of both perineuronal and perisynaptic matrices in the human hippocampus, whose neuronal circuitry is progressively compromised in Alzheimer's disease. We hypothesized that (1) the cellular expression sites of chondroitin sulphate proteoglycan-containing extracellular matrix associate with specific neuronal identities, reflecting network dynamics, and (2) the regional distribution and molecular composition of axonal coats must withstand Alzheimer's disease-related modifications to protect functional synapses. We show by epitope-specific antibodies that the perineuronal protomap of the human hippocampus is distinct from other mammals since pyramidal cells but not calretinin(+) and calbindin(+) interneurons, neurochemically classified as novel neuronal subtypes, lack perineuronal nets. We find that cartilage link protein-1 and brevican-containing matrices form isolated perisynaptic coats, engulfing both inhibitory and excitatory terminals in the dentate gyrus and entorhinal cortex. Ultrastructural analysis revealed that presynaptic neurons contribute components of perisynaptic coats via axonal transport. We demonstrate, by combining biochemical profiling and neuroanatomy in Alzheimer's patients and transgenic (APdE9) mice, the preserved turnover and distribution of axonal coats around functional synapses along dendrite segments containing hyperphosphorylated tau and in amyloid-β-laden hippocampal microdomains. We conclude that the presynapse-driven formation of axonal coats is a candidate mechanism to maintain synapse integrity under neurodegenerative conditions.
    Acta Neuropathologica 09/2012; · 9.73 Impact Factor
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    ABSTRACT: C. Voigt, C. K. Donat, W. Hartig, A. Förschler, M. Skardelly, D. Stichtenoth, T. Arendt, J. Meixensberger and M. U. Schuhmann (2012) Neuropathology and Applied Neurobiology38, 354–366Effect of leukotriene inhibitors on evolution of experimental brain contusionsAims: Leukotriene levels increase in cerebrospinal fluid (CSF) following controlled cortical impact (CCI) injury in rats. We investigated the impact of two different leukotriene inhibitors in the CCI model on CSF leukotriene levels, brain water content (BWC), brain swelling (BS) contusion size and cellular response. Methods: 134 male Sprague Dawley rats were investigated at 4, 24 and 72 h after CCI for CSF leukotriene levels and BWC/BS, lesion size in T2-weighted magnetic resonance imaging and immunohistochemistry. Animals received vehicle, MK-886, an inhibitor of 5-lipoxygenase activating protein, or Boscari®, a mixture of boswellic acids, acting as competitive nonredox 5-lipoxygenase inhibitors before trauma and then every 8 h until sacrifice. Results: The intracranial pressure (ICP) was unaffected by treatment. Boscari treatment reduced CSF leukotriene C4 increase by −45% at 4 h (P < 0.03) and increase of BWC and BS by 49% (P < 0.05) and −58% at 24 h. Treatment with both substances showed a reduction of lesion volume at 72 h by −21% (P < 0.01) in T2-weighted magnetic resonance imaging, which was reflected in a smaller lesion area determined from a NeuN labelled section (−17% to −20%, P < 0.05). Triple immunofluorescence and Fluoro-Jade B staining showed rarefaction of neurones, glia and vasculature in the contusion core, whereas in the pericontusional zone astro- and microglia were upregulated in the presence of dying neurones. Treatment resulted in an improved survival of NeuN labelled neurones in the pericontusional cortex (+15% to +20%, P < 0.05). Conclusions: Leukotriene inhibition should be further investigated as therapeutic option to counteract secondary growth of traumatic brain contusions and to possibly improve pericontusional neuronal survival.
    Neuropathology and Applied Neurobiology 05/2012; 38(4):354 - 366. · 4.84 Impact Factor
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    ABSTRACT: □ HintergrundPatienten mit koronarer Herzerkrankung sind durch thromboembolische Ereignisse besonders gefährdet. Eine Steigerung der Gerinnungsativierung, wie sie durch körperliche Aktivität hervorgerufen werden kann, läßt das Risiko für ein solches Ereignis ansteigen. Die Frage, ob die bei diesen Patienten häufig durchgeführte Fahrradergometrie mit einem erhöhten thromboembolischen Risiko verbunden ist, soll in der vorliegenden Arbeit betrachtet werden. □ Patienten und Methodik49 Patienten (Gruppe 1: mittleres Alter 59 Jahre; 42 Männer, sieben Frauen) mit angiographisch bekannter koronarer Herzerkrankung und 51 Patienten (Gruppe 2: mittleres Alter 53 Jahre; 44 Männer, sieben Frauen) ohne koronare Herzerkrankung wurden einer standardisierten Fahrradergometrie unterzogen. Vor und nach Belastung wurden Parameter der Blutgerinnung und der Fibrinolyse bestimmt. □ ErgebnisseZwischen beiden Gruppen fanden sich für alle vor und nach Belastung bestimmten Parameter keine signifikanten Unterschiede. Allerdings zeigten drei Parameter signifikante Änderungen innerhalb der Gruppen: Faktor VIII erhöhte sich in Gruppe 1 von 132 auf 156% und in Gruppe 2 von 106 auf 136%. Der von-Willebrand-Faktor stieg in Gruppe 1 von 230 auf 249% und in Gruppe 2 von 228 auf 24% an. Als Zeichen einer gesteigerten Fibrinolyse fand sich eine Steigerung des plasminogen-α2-antiplasmin-Komplexes in Gruppe 1 von 251 auf 401 μg/l und in Gruppe 2 von 247 auf 350 μg/l. □ SchlußfolgerungDiese Befunde unterstreichen, daß von der Fahradergometrie, durchgeführt in standardisierter Form und in aerober Stoffwechsellage, kein erhöhtes thromboembolisches Risiko für Patienten mit koronarer Herzerkrankung gegenüber Patienten ohne koronare Herzerkrankung ausgeht. □ BackgroundPhysical exercise leads to an elevated coagulation activity with a possibly disturbed hemostatic balance. Therefore patients with coronary heart disease have a potentially increased risk of thromboembolic events after a bicycle exercise tolerance test, that is frequently performed for diagnostic reasons. □ Patients and MethodsPatients with angiographically known coronary heart disease (Group 1: n=49; age 59 years; male=42, female=7) were investigated in comparison to a healthy cohort (Group 2: n=51; age 53 years; male=44, female=7) to study the influence of a standardized exercise tolerance test on hemostatic variables. Blood samples were taken before and after exercise. □ ResultsNo significant changes were found for any investigated parameter between both groups. However, 3 parameters did change significantly within the groups: factor VIII rose in Group 1 from 132 to 156% and in Group 2 from 106 to 136% and the von Willebrand factor rose in Group 1 from 230 to 249% and in Group 2 from 228 to 247%. An elevated fibrinolytic potential was found with an increase of plasminogen-α2-antiplasmin in Group 1 from 251 to 401 μg/l and in Group 2 from 247 to 350 μg/l. □ ConclusionThe findings underline the clinical presumption that exercise tolerance test does not increase the risk for thromboembolic complications in patients with coronary heart disease in comparison to patients without coronary heart disease, as long as the exercise tolerance test is performed in a standardized way and under aerobe conditions.
    05/2012; 95(1):14-19.

Publication Stats

7k Citations
1,096.75 Total Impact Points

Institutions

  • 1991–2014
    • University of Leipzig
      • • Paul Flechsig Institute for Brain Research
      • • Medizinische Fakultät
      • • Interdisziplinäres Zentrum für Klinische Forschung
      Leipzig, Saxony, Germany
  • 1983–2014
    • Paul-Flechsig-Institut für Hirnforschung
      Leipzig, Saxony, Germany
  • 2006–2011
    • Semmelweis University
      • Department of Anatomy, Histology and Embryology
      Budapest, Budapest fovaros, Hungary
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain
    • Case Western Reserve University
      • Department of Physiology and Biophysics
      Cleveland, OH, United States
  • 2004–2009
    • Max Planck Institute for Evolutionary Anthropology
      • Department of Evolutionary Genetics
      Leipzig, Saxony, Germany
  • 2008
    • University of Cologne
      • Division of General Neurosurgery
      Köln, North Rhine-Westphalia, Germany
    • Otto-von-Guericke-Universität Magdeburg
      • Institute of Biology (IBIO)
      Magdeburg, Saxony-Anhalt, Germany
  • 2007
    • Leibniz Institute for Farm Animal Biology
      Dummerstorf, Mecklenburg-Vorpommern, Germany
  • 2005
    • University of Kuopio
      Kuopio, Eastern Finland Province, Finland
    • Karolinska Institutet
      Solna, Stockholm, Sweden
    • James Cook University
      • Comparative Genomics Centre
      Townsville, Queensland, Australia
  • 2002–2005
    • VU University Medical Center
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
    • Beijing Normal University
      • Department of Biochemistry and Molecular Biology
      Peping, Beijing, China
  • 1987–2003
    • University of Rostock
      • • Gastroenterologie
      • • Institut für Pathologie
      Rostock, Mecklenburg-Vorpommern, Germany
  • 1996–2001
    • Christian-Albrechts-Universität zu Kiel
      • Institut für Medizinische Klimatologie
      Kiel, Schleswig-Holstein, Germany
    • Freie Universität Berlin
      • Department of Psychiatry
      Berlin, Land Berlin, Germany
  • 1989
    • UK Department of Health
      Londinium, England, United Kingdom