Publications by authors named "Martin Krueger"

62 Publications

Large, Stable Spikes Exhibit Differential Broadening in Excitatory and Inhibitory Neocortical Boutons.

Cell Rep 2021 Jan;34(2):108612

Carl-Ludwig-Institute for Physiology, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany. Electronic address:

Presynaptic action potential spikes control neurotransmitter release and thus interneuronal communication. However, the properties and the dynamics of presynaptic spikes in the neocortex remain enigmatic because boutons in the neocortex are small and direct patch-clamp recordings have not been performed. Here, we report direct recordings from boutons of neocortical pyramidal neurons and interneurons. Our data reveal rapid and large presynaptic action potentials in layer 5 neurons and fast-spiking interneurons reliably propagating into axon collaterals. For in-depth analyses, we establish boutons of mature cultured neurons as models for excitatory neocortical boutons, demonstrating that the presynaptic spike amplitude is unaffected by potassium channels, homeostatic long-term plasticity, and high-frequency firing. In contrast to the stable amplitude, presynaptic spikes profoundly broaden during high-frequency firing in layer 5 pyramidal neurons, but not in fast-spiking interneurons. Thus, our data demonstrate large presynaptic spikes and fundamental differences between excitatory and inhibitory boutons in the neocortex.
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http://dx.doi.org/10.1016/j.celrep.2020.108612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809622PMC
January 2021

Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis.

Mol Metab 2021 Mar 7;45:101147. Epub 2021 Jan 7.

RG Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764, Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany; Department of Medicine, Technical University Munich, Munich, Germany. Electronic address:

Objective: Reorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. The objective of this study was to determine whether integrin activity can regulate insulin sensitivity in adipocytes and thereby systemic metabolism.

Methods: We characterized integrin activity in adipose tissue and its consequences on whole-body metabolism using adipose-selective deletion of β1 integrin (Itgb1) and Kindlin-2 (Kind2) in mice.

Results: We demonstrate that integrin signaling regulates white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in a lipodystrophy-like phenotype and systemic insulin resistance. However, brown adipose tissue of Kind2 and Itgb1 mice is chronically hyperactivated and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport.

Conclusions: Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole-body metabolism.
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http://dx.doi.org/10.1016/j.molmet.2020.101147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808956PMC
March 2021

Structural characteristics of oligomers formed by pyroglutamate-modified amyloid β peptides studied by solid-state NMR.

Phys Chem Chem Phys 2020 Jul;22(29):16887-16895

Institute for Medical Physics and Biophysics, Leipzig University Härtelstr. 16-18, D-04107 Leipzig, Germany. and Department of Chemical Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400 005, India.

Neuronal plaques of amyloid β (Aβ) peptides of varying length carrying different posttranslational modifications represent a molecular hallmark of Alzheimer's disease. It is believed that transient oligomeric Aβ assemblies associating in early fibrillation events represent particularly cytotoxic peptide aggregates. Also, N-terminally truncated (in position 3 or 11) and pyroglutamate modified peptides exhibited an increased toxicity compared to the wildtype. In the current study, the molecular structure of oligomeric species of pGlu3-Aβ(3-40) and pGlu11-Aβ(11-40) was investigated using solid-state NMR spectroscopy. On the secondary structure level, for both modified peptides a large similarity between oligomers and mature fibrils of the modified peptides was found mainly based on 13C NMR chemical shift data. Some smaller structural differences were detected in the vicinity of the respective modification site. Also, the crucial early folding molecular contact between residues Phe19 and Leu34 could be observed for the oligomers of both modified peptide species. Therefore, it has to be concluded that the major secondary structure elements of Aβ are already present in oligomers of pGlu3-Aβ(3-40) and pGlu11-Aβ(11-40). These posttranslationally modified peptides arrange in a similar fashion as observed for wild type Aβ(1-40).
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http://dx.doi.org/10.1039/d0cp02307hDOI Listing
July 2020

Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier.

Acta Neuropathol 2020 10 11;140(4):549-567. Epub 2020 Jul 11.

Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood-brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
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http://dx.doi.org/10.1007/s00401-020-02187-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498485PMC
October 2020

Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression.

Thyroid 2020 09 17;30(9):1366-1383. Epub 2020 Apr 17.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany.

Mutations of monocarboxylate transporter 8 (MCT8), a thyroid hormone (TH)-specific transmembrane transporter, cause a severe neurodevelopmental disorder, the Allan-Herndon-Dudley syndrome. In MCT8 deficiency, TH is not able to reach those areas of the brain where TH uptake depends on MCT8. Currently, therapeutic options for MCT8-deficient patients are missing, as TH treatment is not successful in improving neurological deficits. Available data on MCT8 protein and transcript levels indicate complex expression patterns in neural tissue depending on species, brain region, sex, and age. However, information on human MCT8 expression is still scattered and additional efforts are needed to map sites of MCT8 expression in neurovascular units and neural tissue. This is of importance because new therapeutic strategies for this disease are urgently needed. To identify regions and time windows of MCT8 expression, we used highly specific antibodies against MCT8 to perform immunofluorescence labeling of postnatal murine brains, adult human brain tissue, and human cerebral organoids. Qualitative and quantitative analyses of murine brain samples revealed stable levels of MCT8 protein expression in endothelial cells of the bloodbrain barrier (BBB), choroid plexus epithelial cells, and tanycytes during postnatal development. Conversely, the neuronal MCT8 protein expression that was robustly detectable in specific brain regions of young mice strongly declined with age. Similarly, MCT8 immunoreactivity in adult human brain tissue was largely confined to endothelial cells of the BBB. Recently, cerebral organoids emerged as promising models of human neural development and our first analyses of forebrain-like organoids revealed MCT8 expression in early neuronal progenitor cell populations. With respect to MCT8-deficient conditions, our analyses not only strongly support the contention that the BBB presents a lifelong barrier to TH uptake but also highlight the need to decipher the TH transport role of MCT8 in early neuronal cell populations in more detail. Improving the understanding of the spatiotemporal expression in latter barriers will be critical for therapeutic strategies addressing MCT8 deficiency in the future.
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http://dx.doi.org/10.1089/thy.2019.0544DOI Listing
September 2020

Incorporation of the Nonproteinogenic Amino Acid β-Methylamino-alanine Affects Amyloid β Fibril Properties and Toxicity.

ACS Chem Neurosci 2020 04 17;11(7):1038-1047. Epub 2020 Mar 17.

Institute for Medical Physics and Biophysics, Leipzig University, Härtelstr. 16-18, D-04107 Leipzig, Germany.

The nonproteinogenic amino acid β-methylamino alarelevant example for environmental hazards are nonnine (BMAA) is a neurotoxin and represents a potential risk factor for neurodegenerative diseases. Despite intense research over the last years, the pathological mechanism of BMAA is still unclear. One of the main open questions is whether BMAA can be misincorporated into proteins, especially as a substitute for serine, and whether this has structural and functional consequences for the afflicted proteins leading to early onset neurodegeneration. In this study, we hypothesize that BMAA was indeed incorporated into Aβ molecules and study the structural and dynamical consequences of such misincorporation along with the effect such mutated Aβ peptides have on neuronal cells. We used the synthetic β-amyloid peptide (Aβ), a known key player in the development of Alzheimer's disease, to incorporate BMAA substitutions at three different positions in the peptide sequence: SerBMAA at the peptide's N-terminus, PheBMAA in the hydrophobic core region, and SBMAA in the flexible turn region of Aβ fibrils. We performed a set of biophysical experiments including fluorescence, circular dichroism, solid-state NMR spectroscopy, transmission electron microscopy, and X-ray diffraction to investigate structural and functional aspects of the mutated peptides compared to wildtype Aβ. All variants showed high structural tolerance to BMAA misincorporation. In contrast, the cellular response and neuronal survival were affected in a mutation site-specific manner. As a consequence, we can state from the physicochemical point of view that, if BMAA was misincorporated into proteins, it could indeed represent a risk factor that could potentially play a role in neurodegeneration. Further research addressing the role of BMAA, especially its protein-associated form, should be performed to obtain a better understanding of neurodegenerative diseases and to develop new therapeutic strategies.
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http://dx.doi.org/10.1021/acschemneuro.9b00660DOI Listing
April 2020

Gradients in the mammalian cerebellar cortex enable Fourier-like transformation and improve storing capacity.

Elife 2020 02 5;9. Epub 2020 Feb 5.

Carl-Ludwig-Institute for Physiology, Medical Faculty, Leipzig University, Leipzig, Germany.

Cerebellar granule cells (GCs) make up the majority of all neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs in mice. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs than GCs closer to the Purkinje cell layer (outer-zone GCs). Dynamic Clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling dispersion of the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs.
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http://dx.doi.org/10.7554/eLife.51771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002074PMC
February 2020

Simultaneous alterations of oligodendrocyte-specific CNP, astrocyte-specific AQP4 and neuronal NF-L demarcate ischemic tissue after experimental stroke in mice.

Neurosci Lett 2019 10 30;711:134405. Epub 2019 Jul 30.

Department of Neurology, University of Leipzig, Germany. Electronic address:

Ischemic stroke not only affects neurons, but also glial and vascular elements. The development of novel neuroprotective strategies thus requires an improved pathophysiological understanding of ischemia-affected cell types that comprise the 'neurovascular unit' (NVU). To explore spatiotemporal alterations of oligodendrocytes, astrocytes and neurons after experimental ischemic stroke, we applied a permanent middle cerebral artery occlusion model in mice for 4 and 24 h. Using fluorescence microscopy, the oligodendrocyte marker 2',3'-cyclic nucleotide phosphodiesterase (CNP), the neuronal neurofilament light chain (NF-L) and the astroglial aquaporin-4 (AQP4) were analyzed in regional relation to one another. Immunofluorescence intensities of CNP and NF-L were simultaneously increased in the ischemic neocortex and striatum. AQP4 immunoreactivity was decreased in the ischemic striatum, which represents the initial and potentially strongest affected site of infarction. The more distant ischemic neocortex and infarct border zones exhibited areas with alternately increased or decreased AQP4 immunoreactivity, leading to an increase of fluorescence intensity in total. Further, deformed CNP-immunopositive processes were found around axonal spheroids, indicating a combined affection of oligodendrocytes and neurons due to ischemia. Importantly, altered AQP4 immunosignals were not limited to the ischemic core, but were also detectable in penumbral areas. This applies for CNP and NF-L also, since altered immunosignals of all three markers coincided regionally at both time points. In conclusion, the present study provides evidence for a simultaneous affection of oligodendrocytes, astrocytes and neurons after experimental focal cerebral ischemia. Consequently, CNP, AQP4 and NF-L immunofluorescence alterations can be utilized to identify ischemia-affected tissue. The simultaneity of the described alterations further strengthens the concept of interdependent NVU components and distinguishes NF-L, CNP and AQP4 as highly ischemia-sensitive elements. Consequently, future therapeutic approaches might influence stroke evolution via strategies simultaneously addressing both neuronal and glial functions.
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http://dx.doi.org/10.1016/j.neulet.2019.134405DOI Listing
October 2019

Publisher Correction: NRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies.

Nat Commun 2019 Apr 16;10(1):1840. Epub 2019 Apr 16.

Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.

Michael W. Sereda was incorrectly associated with the Department of Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany. The correct affiliations for Michael W. Sereda are Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany and Department of Clinical Neurophysiology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
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http://dx.doi.org/10.1038/s41467-019-09886-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467885PMC
April 2019

NRG1 type I dependent autoparacrine stimulation of Schwann cells in onion bulbs of peripheral neuropathies.

Nat Commun 2019 04 1;10(1):1467. Epub 2019 Apr 1.

Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.

In contrast to acute peripheral nerve injury, the molecular response of Schwann cells in chronic neuropathies remains poorly understood. Onion bulb structures are a pathological hallmark of demyelinating neuropathies, but the nature of these formations is unknown. Here, we show that Schwann cells induce the expression of Neuregulin-1 type I (NRG1-I), a paracrine growth factor, in various chronic demyelinating diseases. Genetic disruption of Schwann cell-derived NRG1 signalling in a mouse model of Charcot-Marie-Tooth Disease 1A (CMT1A), suppresses hypermyelination and the formation of onion bulbs. Transgenic overexpression of NRG1-I in Schwann cells on a wildtype background is sufficient to mediate an interaction between Schwann cells via an ErbB2 receptor-MEK/ERK signaling axis, which causes onion bulb formations and results in a peripheral neuropathy reminiscent of CMT1A. We suggest that diseased Schwann cells mount a regeneration program that is beneficial in acute nerve injury, but that overstimulation of Schwann cells in chronic neuropathies is detrimental.
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http://dx.doi.org/10.1038/s41467-019-09385-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443727PMC
April 2019

Corpora amylacea in human hippocampal brain tissue are intracellular bodies that exhibit a homogeneous distribution of neo-epitopes.

Sci Rep 2019 02 14;9(1):2063. Epub 2019 Feb 14.

Secció de Fisiologia, Departament de Bioquímica i Fisiologia, Universitat de Barcelona, Barcelona, Spain.

Corpora amylacea are spherical bodies of unknown origin and function, which accumulate in the human brain during the aging process and neurodegenerative disorders. In recent work, we reported that they contain some neo-epitopes that are recognized by natural IgMs, revealing a possible link between them and the natural immune system. Here, we performed an ultrastructural study complemented with confocal microscopy in order to shed light on the formation of corpora amylacea and to precisely localize the neo-epitopes. We show that immature corpora amylacea are intracellular astrocytic structures formed by profuse cellular debris and membranous blebs entrapped in a scattered mass of randomly oriented short linear fibers. In mature corpora amylacea, the structure becomes compacted and fibrillary material constitutes the principal component. We also determined that the neo-epitopes were uniformly localized throughout the whole structure. All these observations reinforce the idea that corpora amylacea of human brain are equivalent to another type of polyglucosan bodies named PAS granules, present in mouse brain and originated from degenerative processes. All those findings support the hypothesis that corpora amylacea are involved in the entrapment of damaged materials and non-degradable products and have a role in protective or cleaning mechanisms.
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http://dx.doi.org/10.1038/s41598-018-38010-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375970PMC
February 2019

Endothelial edema precedes blood-brain barrier breakdown in early time points after experimental focal cerebral ischemia.

Acta Neuropathol Commun 2019 02 11;7(1):17. Epub 2019 Feb 11.

Department of Neurology, University Hospital Leipzig, Liebigstr. 20, Leipzig, Germany.

In the setting of stroke, ischemia-related blood-brain barrier (BBB) dysfunction aggravates the cerebral edema, which critically impacts on the clinical outcome. Further, an impaired vascular integrity is associated with the risk of intracranial bleeding, especially after therapeutic recanalization. Therefore, the present study was aimed to investigate early vascular alterations from 30 min to 4 h after experimental middle cerebral artery occlusion (MCAO) in mice. Here, an extravasation of the permeability marker FITC-albumin was detectable in animals 2 and 4 h after MCAO. Thereby, BBB breakdown correlated with alterations of the endothelial surface, indicated by a discontinuous isolectin-B4 staining, while tight junction strands remained detectable using electron and immunofluorescence microscopy. Noteworthy, already 30 min after MCAO, up to 60% of the ischemia-affected vessels showed an endothelial edema, paralleled by edematous astrocytic endfeet, clearly preceding FITC-albumin extravasation. With increasing ischemic periods, scores of vascular damage significantly increased with up to 60% of the striatal vessels showing loss of endothelial integrity. Remarkably, comparison of permanent and transient ischemia did not provide significant differences 4 h after ischemia induction. As these degenerations also involved penumbral areas of potentially salvageable tissue, adjuvant approaches of endothelial protection may help to reduce the vasogenic edema after ischemic stroke.
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http://dx.doi.org/10.1186/s40478-019-0671-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369548PMC
February 2019

Microglia contribute to the glia limitans around arteries, capillaries and veins under physiological conditions, in a model of neuroinflammation and in human brain tissue.

Brain Struct Funct 2019 Apr 31;224(3):1301-1314. Epub 2019 Jan 31.

Institute of Anatomy, Leipzig University, Liebigstraße 13, 04103, Leipzig, Germany.

Microglia represent resident immune cells of the central nervous system (CNS), which have been shown to be involved in the pathophysiology of practically every neuropathology. As microglia were described to participate in the formation of the astroglial glia limitans around CNS vessels, they are part of the neurovascular unit (NVU). Since the NVU is a highly specialized structure, being functionally and morphologically adapted to differing demands in the arterial, capillary, and venous segments, the present study was aimed to systematically investigate the microglial contribution to the glia limitans along the vascular tree. Thereby, the microglial participation in the glia limitans was demonstrated for arteries, capillaries, and veins by immunoelectron microscopy in wild-type mice. Furthermore, analysis by confocal laser scanning microscopy revealed the highest density of microglial endfeet contacting the glial basement membrane around capillaries, with significantly lower densities around arteries and veins. Importantly, this pattern appeared to be unaltered in the setting of experimental autoimmune encephalomyelitis (EAE) in CX3CR1:R26-Tomato reporter mice, although perivascular infiltrates of blood-borne leukocytes predominantly occur at the level of post-capillary venules. However, EAE animals exhibited significantly increased contact sizes of individual microglial endfeet around arteries and veins. Noteworthy, under EAE conditions, the upregulation of MHC-II was not limited to microglia of the glia limitans of veins showing infiltrates of leukocytes, but also appeared at the capillary level. As a microglial contribution to the glia limitans was also observed in human brain tissue, these findings may help characterizing microglial alterations within the NVU in various neuropathologies.
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http://dx.doi.org/10.1007/s00429-019-01834-8DOI Listing
April 2019

Non-pathological Chondrogenic Features of Valve Interstitial Cells in Normal Adult Zebrafish.

J Histochem Cytochem 2019 05 8;67(5):361-373. Epub 2019 Jan 8.

Institute of Anatomy, Faculty of Medicine.

In the heart, unidirectional blood flow depends on proper heart valve function. As, in mammals, regulatory mechanisms of early heart valve and bone development are shown to contribute to adult heart valve pathologies, we used the animal model zebrafish (ZF, Danio rerio) to investigate the microarchitecture and differentiation of cardiac valve interstitial cells in the transition from juvenile (35 days) to end of adult breeding (2.5 years) stages. Of note, light microscopy and immunohistochemistry revealed major differences in ZF heart valve microarchitecture when compared with adult mice. We demonstrate evidence for rather chondrogenic features of valvular interstitial cells by histological staining and immunodetection of SOX-9, aggrecan, and type 2a1 collagen. Collagen depositions are enriched in a thin layer at the atrial aspect of atrioventricular valves and the ventricular aspect of bulboventricular valves, respectively. At the ultrastructural level, the collagen fibrils are lacking obvious periodicity and orientation throughout the entire valve.
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http://dx.doi.org/10.1369/0022155418824083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495486PMC
May 2019

Impaired Neurofilament Integrity and Neuronal Morphology in Different Models of Focal Cerebral Ischemia and Human Stroke Tissue.

Front Cell Neurosci 2018 18;12:161. Epub 2018 Jun 18.

Department of Neurology, University of Leipzig, Leipzig, Germany.

As part of the neuronal cytoskeleton, neurofilaments are involved in maintaining cellular integrity. In the setting of ischemic stroke, the affection of the neurofilament network is considered to mediate the transition towards long-lasting tissue damage. Although peripheral levels of distinct neurofilament subunits are shown to correlate with the clinically observed severity of cerebral ischemia, neurofilaments have so far not been considered for neuroprotective approaches. Therefore, the present study systematically addresses ischemia-induced alterations of the neurofilament light (NF-L), medium (NF-M), and heavy (NF-H) subunits as well as of α-internexin (INA). For this purpose, we applied a multi-parametric approach including immunofluorescence labeling, western blotting, qRT-PCR and electron microscopy. Analyses comprised ischemia-affected tissue from three stroke models of middle cerebral artery occlusion (MCAO), including approaches of filament-based MCAO in mice, thromboembolic MCAO in rats, and electrosurgical MCAO in sheep, as well as human autoptic stroke tissue. As indicated by altered immunosignals, impairment of neurofilament subunits was consistently observed throughout the applied stroke models and in human tissue. Thereby, altered NF-L immunoreactivity was also found to reach penumbral areas, while protein analysis revealed consistent reductions for NF-L and INA in the ischemia-affected neocortex in mice. At the mRNA level, the ischemic neocortex and striatum exhibited reduced expressions of NF-L- and NF-H-associated genes, whereas an upregulation for appeared in the striatum. Further, multiple fluorescence labeling of neurofilament proteins revealed spheroid and bead-like structural alterations in human and rodent tissue, correlating with a cellular edema and lost cytoskeletal order at the ultrastructural level. Thus, the consistent ischemia-induced affection of neurofilament subunits in animals and human tissue, as well as the involvement of potentially salvageable tissue qualify neurofilaments as promising targets for neuroprotective strategies. During ischemia formation, such approaches may focus on the maintenance of neurofilament integrity, and appear applicable as co-treatment to modern recanalizing strategies.
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http://dx.doi.org/10.3389/fncel.2018.00161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015914PMC
June 2018

Ring structure modifications of phenylalanine 19 increase fibrillation kinetics and reduce toxicity of amyloid β (1-40).

Chem Commun (Camb) 2018 May;54(43):5430-5433

Institute for Medical Physics and Biophysics, Leipzig University, Härtelstr. 16-18, Leipzig D-04107, Germany.

We investigated the influence of the chemical structure of the phenylalanine side chain in position 19 of the 40 residue amyloid β peptide. Side chain modifications in this position yielded fibrils of essentially unaltered morphology, structure, and dynamics, but significantly increased fibrillation kinetics and diminished the toxicity of the peptides.
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http://dx.doi.org/10.1039/c8cc01733fDOI Listing
May 2018

Free Heme and Amyloid-β: A Fatal Liaison in Alzheimer's Disease.

J Alzheimers Dis 2018 ;61(3):963-984

Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, Leipzig, Germany.

While the etiology of Alzheimer's disease (AD) is still unknown, an increased formation of amyloid-β (Aβ) peptide and oxidative processes are major pathological mechanism of the disease. The interaction of Aβ with free heme leads to the formation of peroxidase-active Aβ-heme complexes. However, enzyme-kinetic data and systematic mutational studies are still missing. These aspects were addressed in this study to evaluate the role of Aβ-heme complexes in AD. The enzyme-kinetic measurements showed peroxidase-specific pH- and H2O2-dependencies. In addition, the enzymatic activity of Aβ-heme complexes constantly increased at higher peptide excess. Moreover, the role of the Aβ sequence for the named enzymatic activity was tested, depicting human-specific R5, Y10, and H13 as essential amino acids. Also by studying Y10 as an endogenous peroxidase substrate for Aβ-heme complexes, ratio-specific effects were observed, showing an optimal dityrosine formation at an about 40-fold peptide excess. As dityrosine formation promotes Aβ fibrillation while free heme disturbs protein aggregation, we also investigated the effect of Aβ-heme complex-derived peroxidase activity on the formation of Aβ fibrils. The fluorescence measurements showed a different fibrillation behavior at strong peroxidase activity, leading also to altered fibril morphologies. The latter was detected by electron microscopy. As illustrated by selected in vivo measurements on a mouse model of AD, the disease is also characterized by Aβ-derived microvessel destructions and hemolytic processes. Thus, thrombo-hemorrhagic events are discussed as a source for free heme in brain tissue. In summary, we suggest the formation and enzymatic activity of Aβ-heme complexes as pathological key features of AD.
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http://dx.doi.org/10.3233/JAD-170711DOI Listing
January 2019

Amyloid β (1-40) Toxicity Depends on the Molecular Contact between Phenylalanine 19 and Leucine 34.

ACS Chem Neurosci 2018 04 27;9(4):790-799. Epub 2017 Dec 27.

Institute for Medical Physics and Biophysics , Leipzig University , Härtelstr. 16-18 , D-04107 Leipzig , Germany.

The formation of the hydrophobic contact between phenylalanine 19 (F19) and leucine 34 (L34) of amyloid β (1-40) (Aβ(1-40)) is known to be an important step in the fibrillation of Aβ(1-40) peptides. Mutations of this putatively early molecular contact were shown to strongly influence the toxicity of Aβ(1-40) ( Das et al. ( 2015 ) ACS Chem. Neurosci. 6 , 1290 - 1295 ). Any mutation of residue F19 completely abolished the toxicity of Aβ(1-40), suggesting that a proper F19-L34 contact is crucial also for the formation of transient oligomers. In this work, we investigate a series of isomeric substitutions of L34, namely, d-leucine, isoleucine, and valine, to study further details of this molecular contact. These replacements represent very minor alterations in the Aβ(1-40) structure posing the question how these alterations challenge the fibrillation kinetics, structure, dynamics, and toxicity of the Aβ(1-40) aggregates. Our work involves kinetic studies using thioflavin T, transmission electron microscopy, X-ray diffraction for the analysis of the fibril morphology, and nuclear magnetic resonance experiments for local structure and molecular dynamics investigations. Combined with cell toxicity assays of the mutated Aβ(1-40) peptides, the physicochemical and biological importance of the early folding contact between F19 and L34 in Aβ(1-40) is underlined. This implies that the F19-L34 contact influences a broad range of different processes including the initiation of fibrillation, oligomer stability, fibril elongation, local fibril structure, and dynamics and cellular toxicity. These processes do not only cover a broad range of diverse mechanisms, but also proved to be highly sensitive to minor modulations of this crucial contact. Furthermore, our work shows that the contact is not simply mediated by general hydrophobic interactions, but also depends on stereospecific mechanisms.
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http://dx.doi.org/10.1021/acschemneuro.7b00360DOI Listing
April 2018

A novel microglial subset plays a key role in myelinogenesis in developing brain.

EMBO J 2017 11 28;36(22):3292-3308. Epub 2017 Sep 28.

Department of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark

Microglia are resident macrophages of the central nervous system that contribute to homeostasis and neuroinflammation. Although known to play an important role in brain development, their exact function has not been fully described. Here, we show that in contrast to healthy adult and inflammation-activated cells, neonatal microglia show a unique myelinogenic and neurogenic phenotype. A CD11c microglial subset that predominates in primary myelinating areas of the developing brain expresses genes for neuronal and glial survival, migration, and differentiation. These cells are the major source of insulin-like growth factor 1, and its selective depletion from CD11c microglia leads to impairment of primary myelination. CD11c-targeted toxin regimens induced a selective transcriptional response in neonates, distinct from adult microglia. CD11c microglia are also found in clusters of repopulating microglia after experimental ablation and in neuroinflammation in adult mice, but despite some similarities, they do not recapitulate neonatal microglial characteristics. We therefore identify a unique phenotype of neonatal microglia that deliver signals necessary for myelination and neurogenesis.
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http://dx.doi.org/10.15252/embj.201696056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686552PMC
November 2017

Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity.

Cell Metab 2017 Oct 21;26(4):620-632.e6. Epub 2017 Sep 21.

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Ingolstädter Landstraße, 85764 Neuherberg, Germany. Electronic address:

Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.
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http://dx.doi.org/10.1016/j.cmet.2017.08.023DOI Listing
October 2017

Damaged Neocortical Perineuronal Nets Due to Experimental Focal Cerebral Ischemia in Mice, Rats and Sheep.

Front Integr Neurosci 2017 15;11:15. Epub 2017 Aug 15.

Department of Neurology, University of LeipzigLeipzig, Germany.

As part of the extracellular matrix (ECM), perineuronal nets (PNs) are polyanionic, chondroitin sulfate proteoglycan (CSPG)-rich coatings of certain neurons, known to be affected in various neural diseases. Although these structures are considered as important parts of the neurovascular unit (NVU), their role during evolution of acute ischemic stroke and subsequent tissue damage is poorly understood and only a few preclinical studies analyzed PNs after acute ischemic stroke. By employing three models of experimental focal cerebral ischemia, this study was focused on histopathological alterations of PNs and concomitant vascular, glial and neuronal changes according to the NVU concept. We analyzed brain tissues obtained 1 day after ischemia onset from: (a) mice after filament-based permanent middle cerebral artery occlusion (pMCAO); (b) rats subjected to thromboembolic MACO; and (c) sheep at 14 days after electrosurgically induced focal cerebral ischemia. Multiple fluorescence labeling was applied to explore simultaneous alterations of NVU and ECM. Serial mouse sections labeled with the net marker agglutinin (WFA) displayed largely decomposed and nearly erased PNs in infarcted neocortical areas that were demarcated by up-regulated immunoreactivity for vascular collagen IV (Coll IV). Subsequent semi-quantitative analyses in mice confirmed significantly decreased WFA-staining along the ischemic border zone and a relative decrease in the directly ischemia-affected neocortex. Triple fluorescence labeling throughout the three animal models revealed up-regulated Coll IV and decomposed PNs accompanied by activated astroglia and altered immunoreactivity for parvalbumin, a calcium-binding protein in fast-firing GABAergic neurons which are predominantly surrounded by neocortical PNs. Furthermore, ischemic neocortical areas in rodents simultaneously displayed less intense staining of WFA, aggrecan, the net components neurocan, versican and the cartilage link protein (CRTL) as well as markers in net-bearing neurons such as the potassium channel subunit Kv3.1b and neuronal nuclei (NeuN). In summary, theconsistent observations based on three different stroke models confirmed that PNs are highly sensitive constituents of the NVU along with impaired associated GABAergic neurons. These results suggest that PNs could be promising targets of future stroke treatment, and further studies should address their reorganization and plasticity in both stabilizing the acute stroke as well as supportive effects during the chronic phase of stroke.
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http://dx.doi.org/10.3389/fnint.2017.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559442PMC
August 2017

Pyroglutamate-Modified Amyloid β (11- 40) Fibrils Are More Toxic than Wildtype Fibrils but Structurally Very Similar.

Chemistry 2017 Nov 10;23(62):15834-15838. Epub 2017 Oct 10.

Institute for Medical Physics and Biophysics, Leipzig University, Härtelstr. 16-18, 04107, Leipzig, Germany.

The morphology, structure, and dynamics of mature amyloid β (Aβ) fibrils formed by the Aβ variant, which is truncated at residue 11 and chemically modified by enzymatic pyroglutamate formation (pGlu -Aβ(11-40)), was studied along with the investigation of the toxicity of these Aβ variants to neurons and astrocytes. The fibrils of pGlu -Aβ (11-40) were more toxic than wildtype Aβ (1-40) and the longer pGlu3-Aβ (3-40) especially at higher concentration, whereas the overall morphology was quite similar. The secondary structure of pGlu -Aβ (11-40) fibrils shows the typical two β-strands connected by a short turn as known for mature fibrils of Aβ (1-40) and also pGlu -Aβ (3-40). Further insights into tertiary contacts exhibit some similarities of pGlu -Aβ (11-40) fibrils with wildtype Aβ (1-40), but also a so far not described contact between Gly and Ile . This highlights the biological importance of chemical modifications on the molecular structure of Aβ.
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http://dx.doi.org/10.1002/chem.201703909DOI Listing
November 2017

Fatty Acid Oxidation Compensates for Lipopolysaccharide-Induced Warburg Effect in Glucose-Deprived Monocytes.

Front Immunol 2017 29;8:609. Epub 2017 May 29.

Division of Rheumatology, Department of Internal Medicine, University of Leipzig, Leipzig, Germany.

Monocytes enter sites of microbial or sterile inflammation as the first line of defense of the immune system and initiate pro-inflammatory effector mechanisms. We show that activation with bacterial lipopolysaccharide (LPS) induces them to undergo a metabolic shift toward aerobic glycolysis, similar to the Warburg effect observed in cancer cells. At sites of inflammation, however, glucose concentrations are often drastically decreased, which prompted us to study monocyte function under conditions of glucose deprivation and abrogated Warburg effect. Experiments using the Seahorse Extracellular Flux Analyzer revealed that limited glucose supply shifts monocyte metabolism toward oxidative phosphorylation, fueled largely by fatty acid oxidation at the expense of lipid droplets. While this metabolic state appears to provide sufficient energy to sustain functional properties like cytokine secretion, migration, and phagocytosis, it cannot prevent a rise in the AMP/ATP ratio and a decreased respiratory burst. The molecular trigger mediating the metabolic shift and the functional consequences is activation of AMP-activated protein kinase (AMPK). Taken together, our results indicate that monocytes are sufficiently metabolically flexible to perform pro-inflammatory functions at sites of inflammation despite glucose deprivation and inhibition of the LPS-induced Warburg effect. AMPK seems to play a pivotal role in orchestrating these processes during glucose deprivation in monocytes.
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http://dx.doi.org/10.3389/fimmu.2017.00609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447039PMC
May 2017

Stereoisomers Probe Steric Zippers in Amyloid-β.

J Phys Chem B 2017 03 14;121(8):1835-1842. Epub 2017 Feb 14.

Department of Chemical Science, Tata Institute of Fundamental Research , Homi Bhabha Road, Colaba, Mumbai 400005, India.

Shape complementarity between close-packed residues plays a critical role in the amyloid aggregation process. Here, we probe such "steric zipper" interactions in amyloid-β (Aβ), whose aggregation is linked to Alzheimer's disease, by replacing natural residues by their stereoisomers. Such mutations are expected to specifically destabilize the shape sensitive "packing" interactions, which may potentially increase their solubility and change other properties. We study the stereomutants DF19 and DL34 and also the DA2/DF4/DH6/DS8 mutant of Aβ. F19-L34 is a critical contact in a tightly packed region of Aβ, while residues 1-9 are known to be disordered. While both DF19 and DL34 slow down the kinetics of aggregation and form amyloid fibrils efficiently, only DL34 increases the final solubility. DF19 gives rise to additional off-pathway aggregation which results in large, kinetically stable aggregates, and has lower net solubility. DA2/DF4/DH6/DS8 does not have an effect on the kinetics or the solubility. Notably, both DF19 and DL34 oligomers have a significantly lower level of interactions with lipid vesicles and live cells. We conclude that stereoisomers can cause complex site dependent changes in amyloid properties, and provide an effective tool to determine the role of individual residues in shaping the packed interiors of amyloid aggregates.
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http://dx.doi.org/10.1021/acs.jpcb.6b12332DOI Listing
March 2017

Degradation of polystyrene and selected analogues by biological Fenton chemistry approaches: Opportunities and limitations.

Chemosphere 2017 Apr 18;173:520-528. Epub 2017 Jan 18.

Department of Environmental Microbiology, Helmholtz Centre for Environmental Research - UFZ, 04318, Leipzig, Germany. Electronic address:

Conventional synthetic polymers typically are highly resistant to microbial degradation, which is beneficial for their intended purpose but highly detrimental when such polymers get lost into the environment. Polystyrene is one of the most widespread of such polymers, but knowledge about its biological degradability is scarce. In this study, we investigated the ability of the polymer-degrading brown-rot fungus Gloeophyllum trabeum to attack polystyrene via Fenton chemistry driven by the redox-cycling of quinones. Indications of superficial oxidation were observed, but the overall effects on the polymer were weak. To assess factors constraining biodegradation of polystyrene, the small water-soluble model compounds ethylbenzene and isopropylbenzene (cumene) were also subjected to biodegradation by G. trabeum. Likewise, ethylbenzene sulfonate, cumene sulfonate and the dimer 1,3-diphenylbutane sulfonate were used as model compounds for comparison with polystyrene sulfonate, which G. trabeum can substantially depolymerise. All model compounds but cumene were degraded by G. trabeum and yielded a large variety of oxidised metabolites, suggesting that both the very poor bioavailability of polystyrene and its inert basic structure play important roles constraining biodegradability via biologically driven Fenton chemistry.
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http://dx.doi.org/10.1016/j.chemosphere.2017.01.089DOI Listing
April 2017

Influence of the earliest right atrial activation site and its proximity to interatrial connections on P-wave morphology.

Europace 2016 Dec;18(suppl 4):iv35-iv43

Department of Cardiology and The Center for Integrative Electrocardiology at Lund University (CIEL), Universitetssjukhuset, 22185 Lund, Sweden.

Aims: P-wave morphology correlates with the risk for atrial fibrillation (AF). Left atrial (LA) enlargement could explain both the higher risk for AF and higher P-wave terminal force (PTF) in lead V. However, PTF-V has been shown to correlate poorly with LA size. We hypothesize that PTF-V is also affected by the earliest activated site (EAS) in the right atrium and its proximity to inter-atrial connections (IAC), which both show tremendous variability.

Methods And Results: Atrial excitation was triggered from seven different EAS in a cohort of eight anatomically personalized computational models. The posterior IACs were non-conductive in a second set of simulations. Body surface ECGs were computed and separated by left and right atrial contributions. Mid-septal EAS yielded the highest PTF-V. More anterior/superior and more inferior EAS yielded lower absolute PTF-V values deviating by a factor of up to 2.0 for adjacent EAS. Earliest right-to-left activation was conducted via Bachmann's Bundle (BB) for anterior/superior EAS and shifted towards posterior IACs for more inferior EAS. Non-conducting posterior IACs increased PTF-V by up to 150% compared to intact posterior IACs for inferior EAS. LA contribution to the P-wave integral was 24% on average.

Conclusion: The electrical contributor's site of earliest activation and intactness of posterior IACs affect PTF-V significantly by changing LA breakthrough sites independent from LA size. This should be considered for interpretation of electrocardiographical signs of LA abnormality and LA enlargement.
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http://dx.doi.org/10.1093/europace/euw349DOI Listing
December 2016

N-terminal lipid conjugation of amyloid β(1-40) leads to the formation of highly ordered N-terminally extended fibrils.

Phys Chem Chem Phys 2017 Jan;19(3):1839-1846

Institute for Medical Physics and Biophysics, Leipzig University, Härtelstr. 16-18, 04107 Leipzig, Germany.

Fibril formation of amyloid β(1-40) (Aβ(1-40)) peptides N-terminally lipid modified with saturated octanoyl or palmitoyl lipid chains was investigated. Lipid modification of Aβ(1-40) significantly accelerates the fibrillation kinetics of the Aβ peptides as revealed by ThT fluorescence. Electron microscopy and X-ray diffraction results indicate a heterogeneous cross-β structure of the fibrils formed by the lipid-conjugated peptides. Solid-state NMR was used to investigate structural features of these fibrils. The lipid moieties form dynamic and loosely structured heterogeneous lipid assemblies as inferred from H NMR of the deuterated lipid chains. C NMR studies of selected isotopic labels reveals that in addition to Phe and Val, which are part of the canonical cross-β structure, also N-terminal residues (Ala, Phe, Val) are found in β-strand conformation. This suggests that the increased hydrophobicity induced by the lipid modification, alters the energy landscape rendering an N-terminal extension of the β-sheet structure favorable. Furthermore, the fibrils formed by the Aβ-lipid hybrids are much more rigid than wildtype Aβ fibrils as inferred from NMR order parameter measurements. Taken together, increasing the local hydrophobicity of the Aβ N-terminus results in highly ordered but heterogeneous amyloid fibrils with extended N-terminal β-sheet structure.
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http://dx.doi.org/10.1039/c6cp05982aDOI Listing
January 2017

Stroke-induced blood-brain barrier breakdown along the vascular tree - No preferential affection of arteries in different animal models and in humans.

J Cereb Blood Flow Metab 2017 Jul 1;37(7):2539-2554. Epub 2016 Jan 1.

4 Department of Neurology, University Hospital Leipzig, Germany.

Stroke-induced blood-brain barrier breakdown promotes complications like cerebral edema and hemorrhagic transformation, especially in association with therapeutical recanalization of occluded vessels. As arteries, capillaries and veins display distinct functional and morphological characteristics, we here investigated patterns of blood-brain barrier breakdown for each segment of the vascular tree in rodent models of embolic, permanent, and transient middle cerebral artery occlusion, added by analyses of human stroke tissue. Twenty-four hours after ischemia induction, loss of blood-brain barrier function towards FITC-albumin was equally observed for arteries, capillaries, and veins in rodent brains. Noteworthy, veins showed highest ratios of leaky vessels, whereas capillaries exhibited the most and arteries the least widespread perivascular tracer extravasation. In contrast, human autoptic stroke tissue exhibited pronounced extravasations of albumin around arteries and veins, while the pericapillary immunoreactivity appeared only faint. Although electron microscopy revealed comparable alterations of the arterial and capillary endothelium throughout the applied animal models, structural loss of arterial smooth muscle cells was only observed in the translationally relevant model of embolic middle cerebral artery occlusion. In light of the so far available concepts of stroke treatment, the consideration of a differential vascular pathophysiology along the cerebral vasculature is likely to allow development of novel effective treatment strategies.
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http://dx.doi.org/10.1177/0271678X16670922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531350PMC
July 2017

ECG imaging of ventricular tachycardia: evaluation against simultaneous non-contact mapping and CMR-derived grey zone.

Med Biol Eng Comput 2017 Jun 20;55(6):979-990. Epub 2016 Sep 20.

Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Kaiserstr. 12, 76131, Karlsruhe, Germany.

ECG imaging is an emerging technology for the reconstruction of cardiac electric activity from non-invasively measured body surface potential maps. In this case report, we present the first evaluation of transmurally imaged activation times against endocardially reconstructed isochrones for a case of sustained monomorphic ventricular tachycardia (VT). Computer models of the thorax and whole heart were produced from MR images. A recently published approach was applied to facilitate electrode localization in the catheter laboratory, which allows for the acquisition of body surface potential maps while performing non-contact mapping for the reconstruction of local activation times. ECG imaging was then realized using Tikhonov regularization with spatio-temporal smoothing as proposed by Huiskamp and Greensite and further with the spline-based approach by Erem et al. Activation times were computed from transmurally reconstructed transmembrane voltages. The results showed good qualitative agreement between the non-invasively and invasively reconstructed activation times. Also, low amplitudes in the imaged transmembrane voltages were found to correlate with volumes of scar and grey zone in delayed gadolinium enhancement cardiac MR. The study underlines the ability of ECG imaging to produce activation times of ventricular electric activity-and to represent effects of scar tissue in the imaged transmembrane voltages.
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http://dx.doi.org/10.1007/s11517-016-1566-xDOI Listing
June 2017

Fibrils of Truncated Pyroglutamyl-Modified Aβ Peptide Exhibit a Similar Structure as Wildtype Mature Aβ Fibrils.

Sci Rep 2016 09 21;6:33531. Epub 2016 Sep 21.

Institute for Medical Physics and Biophysics, Leipzig University Härtelstr. 16-18, D-04107 Leipzig, Germany.

Fibrillation of differently modified amyloid β peptides and deposition as senile plaques are hallmarks of Alzheimer's disease. N-terminally truncated variants, where the glutamate residue 3 is converted into cyclic pyroglutamate (pGlu), form particularly toxic aggregates. We compare the molecular structure and dynamics of fibrils grown from wildtype Aβ(1-40) and pGlu3-Aβ(3-40) on the single amino acid level. Thioflavin T fluorescence, electron microscopy, and X-ray diffraction reveal the general morphology of the amyloid fibrils. We found good agreement between the (13)C and (15)N NMR chemical shifts indicative for a similar secondary structure of both fibrils. A well-known interresidual contact between the two β-strands of the Aβ fibrils could be confirmed by the detection of interresidual cross peaks in a (13)C-(13)C NMR correlation spectrum between the side chains of Phe 19 and Leu 34. Small differences in the molecular dynamics of residues in the proximity to the pyroglutamyl-modified N-terminus were observed as measured by DIPSHIFT order parameter experiments.
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http://dx.doi.org/10.1038/srep33531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030707PMC
September 2016