Thomas Arendt

Paul-Flechsig-Institut für Hirnforschung, Leipzig, Saxony, Germany

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Publications (331)1186.12 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
  • PLoS ONE 03/2015; 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; DOI:10.1016/j.ijdevneu.2015.03.003 · 2.03 Impact Factor
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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; 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; 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.
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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: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 · 4.84 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 (BBA) - Molecular Basis of Disease 06/2014; 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: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
  • Neurobiology of aging 11/2013; 35(4). DOI:10.1016/j.neurobiolaging.2013.09.042 · 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; 39(2). DOI:10.3233/JAD-131535 · 3.61 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; 305(5). DOI:10.1152/ajpregu.00117.2013 · 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; 34(11). DOI:10.1016/j.neurobiolaging.2013.05.008 · 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; 48(3). DOI:10.1007/s12035-013-8445-3 · 5.29 Impact Factor

Publication Stats

9k Citations
1,186.12 Total Impact Points

Institutions

  • 1983–2015
    • Paul-Flechsig-Institut für Hirnforschung
      Leipzig, Saxony, Germany
  • 1992–2014
    • University of Leipzig
      • • Paul Flechsig Institute for Brain Research
      • • Interdisciplinary Centre for Clinical Research
      • • Institute of Biochemistry
      Leipzig, Saxony, Germany
  • 2009
    • Max Planck Institute for Evolutionary Anthropology
      Leipzig, Saxony, Germany
  • 2007
    • Leibniz Institute for Farm Animal Biology
      Dummerstorf, Mecklenburg-Vorpommern, Germany
  • 2005
    • Karolinska Institutet
      Solna, Stockholm, Sweden
  • 2002–2005
    • VU University Medical Center
      • • Department of Psychiatry
      • • Department of Pathology
      Amsterdamo, North Holland, Netherlands
  • 1995–2005
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 2004
    • University of Kuopio
      Kuopio, Northern Savo, Finland
    • Monash University (Australia)
      Melbourne, Victoria, Australia
  • 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