Thomas Arendt

University of Leipzig, Leipzig, Saxony, Germany

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Publications (340)1209.94 Total impact

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    ABSTRACT: Alzheimer's disease (AD) is a degenerative disorder where the distribution of pathology throughout the brain is not random but follows a predictive pattern used for pathological staging. While the involvement of defined functional systems is fairly well established for more advanced stages, the initial sites of degeneration are still ill defined. The prevailing concept suggests an origin within the transentorhinal and entorhinal cortex (EC) from where pathology spreads to other areas. Still, this concept has been challenged recently suggesting a potential origin of degeneration in nonthalamic subcortical nuclei giving rise to cortical innervation such as locus coeruleus (LC) and nucleus basalis of Meynert (NbM). To contribute to the identification of the early site of degeneration, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of AD. To this end, we stereologically assessed neurone counts in the NbM, LC and EC layer-II in the same AD patients ranging from preclinical stages to severe dementia. In all three areas, neurone loss becomes detectable already at preclinical stages and is clearly manifest at prodromal AD/MCI. At more advanced AD, cell loss is most pronounced in the NbM > LC > layer-II EC. During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area. We can thus not rule out that there is more than one way of spreading from its site of origin or that degeneration even occurs independently at several sites in parallel.
    12/2015; 3(1). DOI:10.1186/s40478-015-0187-1
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    ABSTRACT: The extracellular matrix is an integral part of the neural tissue. Its most conspicuous manifestation in the brain are the perineuronal nets (PNs) which surround somata and proximal dendrites of distinct neuron types. The chondroitin sulfate proteoglycan brevican is a major component of PNs. In contrast to other PN-comprising proteoglycans (e.g. aggrecan and neurocan), brevican is mainly expressed in the perisynaptic space closely associated with both the pre- and postsynaptic membrane. This specific localization prompted the hypothesis that brevican might play a role in synaptic transmission. In the present study we specifically investigated the role of brevican in synaptic transmission at a central synapse, the calyx of Held in the medial nucleus of the trapezoid body by the use of in vivo electrophysiology, immunohistochemistry, biochemistry and electron microscopy. In vivo extracellular single-unit recordings were acquired in brevican-deficient mice and the dynamics and reliability of synaptic transmission were compared to wildtype littermates. In knockout mice, the speed of pre-to-postsynaptic action potential (AP) transmission was reduced and the duration of the respective pre- and postsynaptic APs increased. The reliability of signal transmission, however, was not affected by the lack of brevican. The changes in dynamics of signal transmission were accompanied by the reduction of (i) presynaptic vGlut1 and (ii) the size of subsynaptic cavities. The present results suggest an essential role of brevican for the functionality of high-speed synaptic transmission at the calyx of Held. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 07/2015; DOI:10.1113/JP270849 · 4.54 Impact Factor
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    ABSTRACT: Neurons are postmitotic cells that are in permanent cell cycle arrest. However, components of the cell cycle machinery that are expressed in Alzheimer 's disease (AD) neurons are showing features of a cycling cell and those attributed to a postmitotic cell as well. Furthermore, the unique physiological operations taking place in neurons, ascribed to "core cell cycle regulators" are also key regulators in cell division. Functions of these cell cycle regulators include neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. In this review, we focus on cohesion and cohesion related proteins in reference to their neuronal functions and how impaired centromere/cohesion dynamics may connect cell cycle dysfunction to aneuploidy in AD. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience & Biobehavioral Reviews 05/2015; 55. DOI:10.1016/j.neubiorev.2015.05.010 · 10.28 Impact Factor
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    ABSTRACT: Electroporation is a useful technique to study gene function during development but its broad application is hampered due to the expensive equipment needed. We describe the construction of a transportable, simple and inexpensive electroporator delivering square pulses with varying length and amplitude. The device was successfully used for in utero electroporation in mouse with a performance comparable to that of commercial products. © 2015 Japanese Society of Developmental Biologists.
    Development Growth and Regeneration 05/2015; 57(5). DOI:10.1111/dgd.12216 · 2.18 Impact Factor
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    PLoS ONE 03/2015; 10(3). DOI:10.1371/journal.pone.0119423 · 3.53 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor (VEGF) has been characterized as a heparin binding angiogenic growth factor displaying high specificity for endothelial cells. It is profoundly accumulated and co-localized with amyloid beta (Aβ) plaques in the brain of Alzheimer's disease patients. In order to examine the effect of Aβ plaques on the expression level of VEGF mRNA and its receptors, brain tissue of both transgenic Tg2576 and wild type mice at ages ranging from 13 to 22 months was subjected to in situ hybridization followed by densitometric assessment using computer-assisted image analysis. Strong expression of VEGF mRNA, fetal liver kinase (Flk)-1 mRNA, and neuropilin (Nrp)-1 mRNA in the piriform, entorhinal, somatosensory, frontal cortex and hippocampal formation of both transgenic and non-transgenic mice brain was detected. Developmentally, only expression of VEGF mRNA was increased with age in the entorhinal, and somatosensory cortex of wild type mice. In 20-month-old transgenic Tg2576 mice, up-regulation of VEGF mRNA, Flk-1 mRNA, and Nrp-1 mRNA transcripts was observed in the entorhinal cortex compared to age-matched wild type mice. Our data suggest up-regulation of VEGF mRNA, Flk-1 mRNA and Nrp-1 mRNA, at least in the entorhinal cortex at ages when Aβ deposition in Tg2576 is typically increasing. Copyright © 2015. Published by Elsevier Ltd.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 03/2015; 43. DOI:10.1016/j.ijdevneu.2015.03.003 · 2.92 Impact Factor
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    ABSTRACT: Aging is the main risk factor for Alzheimer's disease (AD). With aging, inflammation has been recognized as potential trigger for starting the neurodegenerative cascade leading to neuronal death. Before Aβ and tau accumulation, evidence has put alterations of the cell cycle at the core of these processes. Still, a number of features of the cell cycle re-entry phenotype have remained elusive to the role of ectopic protein expression in the process of neuroinflammation and consequently neuronal cell death. Recently, a novel cyclin dependent kinase CDK11 has been found to be involved in astrocyte mediated inflammatory response and Alzheimer's disease. In this review, we aim to establish the missing part of the puzzle between neuroinflammation and APP / Aβ deregulation in AD by evaluating the role of a cyclin, CDK11. CDK11 may play a vital role in cell cycle re-entry in AD neurons in an APP-dependent manner, thus presenting an intriguing novel function of the APP signaling pathway in AD.
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    ABSTRACT: The brains of Alzheimer's disease (AD) patients are characterized by deposits of Abeta peptides and by accompanying chronic inflammation. Here, we provide evidence that the enzyme isoglutaminyl cyclase (isoQC) is a novel factor contributing to both aspects of AD pathology. Two putative substrates of isoQC, N-truncated Abeta peptides and the monocyte chemoattractant chemokine CCL2, undergo isoQC-catalyzed pyroglutamate (pGlu) modification. This triggers Abeta aggregation and facilitates the biological activity of CCL2, which collectively results in the formation of high molecular weight Abeta aggregates, glial cell activation, neuroinflammation and neuronal cell death. In mouse brain, we found isoQC to be neuron-specifically expressed in neocortical, hippocampal and subcortical structures, localized to the endoplasmic reticulum and Golgi apparatus as well as co-expressed with its substrate CCL2. In aged APP transgenic Tg2576 mice, both isoQC and CCL2 mRNA levels are up-regulated and isoQC and CCL2 proteins were found to be co-induced in Abeta plaque-associated reactive astrocytes. Also, in mouse primary astrocyte culture, a simultaneous up-regulation of isoQC and CCL2 expression was revealed upon Abeta and pGlu-Abeta stimulation. In brains of AD patients, the expression of isoQC and CCL2 mRNA and protein is up-regulated compared to controls and correlates with pGlu-Abeta load and with the decline in mini-mental state examination. Our observations provide evidence for a dual involvement of isoQC in AD pathogenesis by catalysis of pGlu-Abeta and pGlu-CCL2 formation which mutually stimulate inflammatory events and affect cognition. We conclude that isoQC inhibition may target both major pathological events in the development of AD.
    Acta Neuropathologica 02/2015; 129(4). DOI:10.1007/s00401-015-1395-2 · 9.78 Impact Factor
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    ABSTRACT: Oxidative stress is thought to be one of the main mediators of neuronal damage in human neurodegenerative disease. Still, the dissection of causal relationships has turned out to be remarkably difficult. Here, we have analyzed global protein oxidation in terms of carbonylation of membrane proteins and cytoplasmic proteins in three different mammalian species: aged human cortex and cerebellum from patients with or without Alzheimer’s disease, mouse cortex and cerebellum from young and old animals, and adult rat hippocampus and cortex subjected or not subjected to cerebral ischemia. Most tissues showed relatively similar levels of protein oxidation. However, human cortex was affected by severe membrane protein oxidation, while exhibiting lower than average cytoplasmic protein oxidation. In contrast, ex vivo autooxidation of murine cortical tissue primarily induced aqueous protein oxidation, while in vivo biological aging or cerebral ischemia had no major effect on brain protein oxidation. The unusually high levels of membrane protein oxidation in the human cortex were also not predicted by lipid peroxidation, as the levels of isoprostane immunoreactivity in human samples were considerably lower than in rodent tissues. Our results indicate that the aged human cortex is under steady pressure from specific and potentially detrimental membrane protein oxidation. The pronounced difference between humans, mice and rats regarding the primary site of cortical oxidation might have contributed to the unresolved difficulties in translating into therapies the wealth of data describing successful antioxidant neuroprotection in rodents.
    12/2014; 97. DOI:10.1016/j.redox.2014.12.013
  • Thomas Arendt, Jens Stieler, Max Holzer
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    ABSTRACT: Sporadic Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder of unknown cause characterized by fibrillar accumulation of the Aß-peptide and aggregates of the microtubule-associated protein tau in a hyperphosphorylated form. Already at preclinical stages, AD is characterized by hypometabolic states which are a good predictor of cognitive decline. Here, we summarize recent evidence derived from the study of hibernating animals that brain hypometabolism can trigger PHF-like hyperphosphorylation of tau. We put forward the concept that particular types of neurons respond to a hypometabolic state with an elevated phosphorylation of tau protein which represents a physiological mechanism involved in regulating synaptic gain. If, in contrast to hibernation, the hypometabolic state is not terminated after a definite time but rather persists and progresses, the elevated phosphorylation of tau protein endures and the protective reaction associated with it might turn into a pathological cascade leading to neurodegeneration.
    Journal of Neural Transmission 12/2014; 122(4). DOI:10.1007/s00702-014-1342-8 · 2.87 Impact Factor
  • Anne Suttkus, Markus Morawski, Thomas Arendt
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    ABSTRACT: The extracellular matrix (ECM) of the central nervous system (CNS) occupies a large part of the neural tissue. It serves a variety of functions ranging from support of cell migration and regulating synaptic transmission and plasticity to the active modulation of the neural tissue after injury. In addition, evidence for neuroprotective properties of ECM components has accumulated more recently. In contrast to other connective tissues, the central nervous ECM is mainly composed of glycosaminoglycans, which can be present unbound in the form of hyaluronan or bound to proteins, thus forming proteoglycans. A subtype of this molecular family are the chondroitin sulphate proteoglycans (CSPGs), which are composed of a core protein that carries at least one covalently bound glycosaminoglycan side chain with a certain degree of sulphation. Several studies could show neuroprotective features of CSPGs against excitotoxicity, amyloid-ß toxicity, or oxidative stress. Recently, we could provide evidence for a neuroprotective function of a specialized form of ECM, the so-called perineuronal net ensheathing a subtype of neurons. Here, we will give an overview on recently emerging aspects of neuroprotective properties of CSPGs and perineuronal nets that might be relevant for our understanding on the distribution and progression of brain pathology and future perspectives toward modifying neurodegenerative diseases.
    Molecular Neurobiology 11/2014; · 5.29 Impact Factor
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    ABSTRACT: Reduction of beta-catenin (CTNNB1) destroying complex components, e.g. adenomatous polyposis coli (APC), induces beta-catenin signaling and subsequently triggers activation of genes involved in proliferation and tumorigenesis. Though diminished expression of APC has organ specific and threshold dependent influence on the development of liver tumors in mice, the molecular basis is poorly understood. Therefore, a detailed investigation was conducted to determine the underlying mechanism in the development of liver tumors under reduced APC levels. Mouse liver at different developmental stages was analyzed in terms of beta-catenin target genes including Cyp2e1, Glul and Ihh using real-time RT-PCR, reporter gene assays and immunohistological methods with consideration of liver zonation. Data from human livers with mutations in APC derived from FAP patients were also included. Hepatocyte senescence was investigated by determining p16(INK4a) expression level, presence of senescence-associated beta-galactosidase (SA-beta-Gal) activity and assessing ploidy. A beta-catenin activation of hepatocytes does not always result in beta-catenin positivity but unexpectedly also in mixed and beta-catenin negative tumors. In summary, a senescence inducing program was found in hepatocytes with increased beta-catenin levels and a positive selection of hepatocytes lacking p16(INK4a), by epigenetic silencing, drives the development of liver tumors in mice with reduced APC expression (Apc(580S) mice). The lack of p16(INK4a) was also detected in liver tumors of mice with triggers other than APC reduction. Implications: Epigenetic silencing of p16(Ink4a) in selected liver cells bypassing senescence is a general principle for development of liver tumors with beta-catenin involvement in mice independent of the initial stimulus.
    Molecular Cancer Research 09/2014; 13(2). DOI:10.1158/1541-7786.MCR-14-0278-T · 4.50 Impact Factor
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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 07/2014; 5(7):e1353. DOI:10.1038/cddis.2014.317 · 5.18 Impact Factor
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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; DOI:10.1111/nan.12163 · 4.97 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 06/2014; 1842(9). DOI:10.1016/j.bbadis.2014.05.029 · 5.09 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 03/2014; 5(3):e1119. DOI:10.1038/cddis.2014.25 · 5.18 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; · 5.09 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; 18(1). DOI:10.1179/1476830513Z.000000000112 · 2.11 Impact Factor

Publication Stats

10k Citations
1,209.94 Total Impact Points

Institutions

  • 1992–2015
    • University of Leipzig
      • • Paul Flechsig Institute for Brain Research
      • • Interdisciplinary Centre for Clinical Research
      • • Faculty of Medicine
      • • Institute of Biochemistry
      Leipzig, Saxony, Germany
  • 1983–2015
    • Paul-Flechsig-Institut für Hirnforschung
      Leipzig, Saxony, Germany
  • 2004–2005
    • VU University Medical Center
      • Department of Psychiatry
      Amsterdamo, North Holland, Netherlands
    • University of Kuopio
      Kuopio, Northern Savo, Finland
    • Monash University (Australia)
      Melbourne, Victoria, Australia
  • 1995–2005
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, 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
  • 1987–1989
    • University of Rostock
      • Institut für Pathologie
      Rostock, Mecklenburg-Vorpommern, Germany