30 results on '"Angelos Skodras"'
Search Results
2. Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions
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Gaye Tanriöver, Mehtap Bacioglu, Manuel Schweighauser, Jasmin Mahler, Bettina M. Wegenast-Braun, Angelos Skodras, Ulrike Obermüller, Melanie Barth, Deborah Kronenberg-Versteeg, K. Peter R. Nilsson, Derya R. Shimshek, Philipp J. Kahle, Yvonne S. Eisele, and Mathias Jucker
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Synuclein ,Microglia ,Inclusion ,Prion-like ,Amyloid ,Conformation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human α-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of α-synucleinopathy bears importance for mechanistic and preclinical-translational studies.
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- 2020
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3. Long-term adult human brain slice cultures as a model system to study human CNS circuitry and disease
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Niklas Schwarz, Betül Uysal, Marc Welzer, Jacqueline C Bahr, Nikolas Layer, Heidi Löffler, Kornelijus Stanaitis, Harshad PA, Yvonne G Weber, Ulrike BS Hedrich, Jürgen B Honegger, Angelos Skodras, Albert J Becker, Thomas V Wuttke, and Henner Koch
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adult human neurons ,morphology ,human brain slice cultures ,spines ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Most of our knowledge on human CNS circuitry and related disorders originates from model organisms. How well such data translate to the human CNS remains largely to be determined. Human brain slice cultures derived from neurosurgical resections may offer novel avenues to approach this translational gap. We now demonstrate robust preservation of the complex neuronal cytoarchitecture and electrophysiological properties of human pyramidal neurons in long-term brain slice cultures. Further experiments delineate the optimal conditions for efficient viral transduction of cultures, enabling ‘high throughput’ fluorescence-mediated 3D reconstruction of genetically targeted neurons at comparable quality to state-of-the-art biocytin fillings, and demonstrate feasibility of long term live cell imaging of human cells in vitro. This model system has implications toward a broad spectrum of translational studies, regarding the validation of data obtained in non-human model systems, for therapeutic screening and genetic dissection of human CNS circuitry.
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- 2019
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4. Computer-generated ovaries to assist follicle counting experiments.
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Angelos Skodras and Gianluca Marcelli
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Medicine ,Science - Abstract
Precise estimation of the number of follicles in ovaries is of key importance in the field of reproductive biology, both from a developmental point of view, where follicle numbers are determined at specific time points, as well as from a therapeutic perspective, determining the adverse effects of environmental toxins and cancer chemotherapeutics on the reproductive system. The two main factors affecting follicle number estimates are the sampling method and the variation in follicle numbers within animals of the same strain, due to biological variability. This study aims at assessing the effect of these two factors, when estimating ovarian follicle numbers of neonatal mice. We developed computer algorithms, which generate models of neonatal mouse ovaries (simulated ovaries), with characteristics derived from experimental measurements already available in the published literature. The simulated ovaries are used to reproduce in-silico counting experiments based on unbiased stereological techniques; the proposed approach provides the necessary number of ovaries and sampling frequency to be used in the experiments given a specific biological variability and a desirable degree of accuracy. The simulated ovary is a novel, versatile tool which can be used in the planning phase of experiments to estimate the expected number of animals and workload, ensuring appropriate statistical power of the resulting measurements. Moreover, the idea of the simulated ovary can be applied to other organs made up of large numbers of individual functional units.
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- 2015
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5. Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease
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Jessica Wagner, Karoline Degenhardt, Marleen Veit, Nikolaos Louros, Katerina Konstantoulea, Angelos Skodras, Katleen Wild, Ping Liu, Ulrike Obermüller, Vikas Bansal, Anupriya Dalmia, Lisa M. Häsler, Marius Lambert, Matthias De Vleeschouwer, Hannah A. Davies, Jillian Madine, Deborah Kronenberg-Versteeg, Regina Feederle, Domenico Del Turco, K. Peter R. Nilsson, Tammaryn Lashley, Thomas Deller, Marla Gearing, Lary C. Walker, Peter Heutink, Frederic Rousseau, Joost Schymkowitz, Mathias Jucker, and Jonas J. Neher
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PROVIDES ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,metabolism [Amyloid beta-Peptides] ,tau Proteins ,Plaque, Amyloid ,Mice, Transgenic ,Mice ,Amyloid beta-Protein Precursor ,MOUSE MODELS ,Alzheimer Disease ,metabolism [Amyloid beta-Protein Precursor] ,ANGIOPATHY ,Humans ,Animals ,Cognitive Dysfunction ,PEPTIDE ,NETWORK ,BRAIN ,DEPOSITION ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,A-BETA ,Serum Amyloid A Protein ,Amyloid beta-Peptides ,Science & Technology ,Multidisciplinary ,Middle Aged ,metabolism [Plaque, Amyloid] ,metabolism [tau Proteins] ,Multidisciplinary Sciences ,PATHOLOGY ,MICE ,Science & Technology - Other Topics ,ddc:500 ,metabolism [Alzheimer Disease] - Abstract
Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain. Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain. ispartof: Nature vol:612 issue:7938 pages:123-131 ispartof: location:England status: published
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- 2022
6. Second Harmonic Generation Microscopy as a Novel Intraoperative Assessment of Rat Median Nerve Injury
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Matthew J. Gluck, Christina M. Beck, Angelos Skodras, Zachary L. Bernstein, Todd A. Rubin, Michael R. Hausman, and Paul J. Cagle
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Orthopedics and Sports Medicine ,Surgery - Abstract
Nerves that are functionally injured but appear macroscopically intact pose the biggest clinical dilemma. Second Harmonic Generation (SHG) Microscopy may provide a real-time assessment of nerve damage, with the ultimate goal of allowing surgeons to accurately quantify the degree of nerve damage present. The aim of this study was to demonstrate the utility of SHG microscopy to detect nerve damage in vivo in an animal model.Ten Sprague-Dawley rats were anesthetized and prepared for surgery. After surgical exposure and using a custom-made stretch applicator, the right median nerves were stretched by 20%, corresponding to a high strain injury, and held for 5 minutes. The left median nerve served as a sham control (SC), only being placed in the applicator for 5 minutes with no stretch. A nerve stimulator was used to assess the amount of stimulation required to induce a flicker and contraction of the paw. Nerves were then imaged using a multiphoton laser scanning microscope.Immediately after injury (day 0), SHG images of SC median nerves exhibited parallel collagen fibers with linear, organized alignment. In comparison with SC nerves, high strain nerves demonstrated artifacts indicative of nerve damage consisting of wavy, undulating fibers with crossing fibers and tears, as well as a decrease in the linear organization, which correlated with an increase in the mean stimulation required to induce a flicker and contraction of the paw.Second Harmonic Generation microscopy may provide the ability to detect an acute neural stretch injury in the rat median nerve. Epineurial collagen disorganization correlated with the stimulation required for nerve function.In the future, SHG may provide the ability to visualize nerve damage intraoperatively, allowing for better clinical decision-making. However, this is currently a research tool and requires further validation before translating to the clinical setting.
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- 2022
7. Quantitative organization of the excitatory synapses of the primate cerebellar nuclei: further evidence for a specialized architecture underlying the primate cerebellum
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Salah Hamodeh, Angelos Skodras, Fahad Sultan, and Haian Mao
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Male ,Cerebellum ,Histology ,Vesicular glutamate transporter 1 ,Presynaptic Terminals ,Quantitative immunofluorescence ,Deep cerebellar nuclei ,Macaque ,050105 experimental psychology ,03 medical and health sciences ,0302 clinical medicine ,biology.animal ,medicine ,Animals ,0501 psychology and cognitive sciences ,Primate ,Lipofuscin fluorescence removal ,Neurons ,biology ,General Neuroscience ,fungi ,05 social sciences ,Neurosciences ,Dendrites ,Comparative neuroanatomy ,Macaca mulatta ,Axons ,Dentate nucleus ,medicine.anatomical_structure ,Cerebellar Nuclei ,nervous system ,Synapses ,Vesicular glutamate transporter ,biology.protein ,Excitatory postsynaptic potential ,Original Article ,Neuron ,Anatomy ,Neuroscience ,Neurovetenskaper ,030217 neurology & neurosurgery - Abstract
The cerebellar intrinsic connectivity is of remarkable regularity with a similar build repeated many times over. However, several modifications of this basic circuitry occur that can provide important clues to evolutionary adaptations. We have observed differences in the wiring of the cerebellar output structures (the deep cerebellar nuclei, DCN) with higher dendritic length density in the phylogenetically newer DCN. In rats, we showed that an increase in wiring is associated with an increase in the presynaptic vesicular glutamate transporter 1 (vGluT1). In this study, we have extended our analysis to the rhesus monkey and can show similarities and differences between the two species. The similarities confirm a higher density in vGluT1+ boutons in the lateral (LN/dentate) and posterior interpositus nucleus compared to the phylogenetically older DCN. In general, we also observe a lower density of vGluT1 and 2+ boutons in the monkey, which however, yields a similar number of excitatory boutons per neuron in both species. The only exception is the vGlut1+ boutons in the macaque LN/dentate, which showed a significantly lower number of vGluT1+ boutons per neuron. We also detected a higher percentage of co-labelled vGluT1 and 2 boutons in the macaque than we found in the rat. In summary, these results confirm that the hyposcalled dendrites of the monkey LN/dentate also show a lower number of vGluT1+ boutons per neuron. These results provide further support of our model relating the dendritic morphology of the LN/dentate neurons to the morphology of the specially enlarged LN/dentate nucleus in primates. Electronic supplementary material The online version of this article (10.1007/s00429-019-01888-8) contains supplementary material, which is available to authorized users.
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- 2019
8. Medin amyloid forms age‐associated aggregates in the brain vasculature and may contribute to cerebral β‐amyloidosis
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Angelos Skodras, Anna Julia Koppelmann, Jillian Madine, Katleen Wild, Lisa M. Haesler, Felix von Zweydorf, Karoline Degenhardt, Rusheka Maxwell, Philipp J. Kahle, Domenico Del Turco, Ulrike Obermüller, Thomas Deller, Mathias Jucker, Christian Johannes Gloeckner, Jonas J. Neher, Hannah A. Davies, Jessica Wagner, and Carola Rotermund
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Pathology ,medicine.medical_specialty ,Brain vasculature ,Amyloid ,Epidemiology ,business.industry ,Health Policy ,Amyloidosis ,medicine.disease ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,medicine ,Neurology (clinical) ,Geriatrics and Gerontology ,business - Published
- 2020
9. Sirtuin-1 Sensitive Lysine-136 Acetylation Drives Phase Separation and Pathological Aggregation of TDP-43
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Jorge Garcia Morato, Manuela Neumann, Christian Johannes Gloeckner, Angelos Skodras, Friederike Hans, Simon J Elsaesser, Felix von Zweydorf, Emanuele Buratti, Regina Feederle, and Philipp J. Kahle
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Lysine ,Protein Aggregation, Pathological ,metabolism [Protein Aggregation, Pathological] ,Sirtuin 1 ,Ubiquitin ,mental disorders ,Humans ,biology ,Chemistry ,metabolism [Amyotrophic Lateral Sclerosis] ,metabolism [Sirtuin 1] ,Amyotrophic Lateral Sclerosis ,nutritional and metabolic diseases ,RNA ,Acetylation ,metabolism [Lysine] ,nervous system diseases ,Cell biology ,DNA-Binding Proteins ,genetics [Sirtuin 1] ,metabolism [RNA] ,RNA splicing ,Sirtuin ,biology.protein ,ddc:500 ,metabolism [DNA-Binding Proteins] ,Nuclear transport ,Protein Processing, Post-Translational - Abstract
The trans-activation response DNA-binding protein TDP-43 regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Confirming the results from site-directed mutagenesis, we succeeded to introduce authentic acetyl-lysine at the identified sites via amber suppression. [AcK84]TDP-43 showed cytoplasmic mislocalization and the aggregation propensity of [acK136]TDP-43 was confirmed. With newly developed antibodies, we found that the nuclear sirtuin SIRT1 can potently deacetylate [acK136]TDP-43. Moreover, SIRT1 reduced the aggregation propensity of [acK136]TDP-43. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting novel regulatory mechanisms for TDP-43 pathogenesis.
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- 2020
10. Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice
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Philipp J. Kahle, Rusheka Maxwell, Katleen Wild, Regina Feederle, Jasmin K Hefendehl, Jonas J. Neher, Felix von Zweydorf, Domenico Del Turco, Hannah A. Davies, Karoline Degenhardt, Anna Julia Koppelmann, Thomas Deller, Mathias Jucker, Tammaryn Lashley, Christian Johannes Gloeckner, Jessica Wagner, Michael Candlish, Carola Rotermund, Jillian Madine, and Angelos Skodras
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metabolism [Milk Proteins] ,Male ,genetics [Amyloid] ,Aging ,Brain vasculature ,metabolism [Vascular Diseases] ,Mice ,MFGE8 protein, human ,Aorta ,Aged, 80 and over ,education.field_of_study ,metabolism [Antigens, Surface] ,Multidisciplinary ,physiology [Brain Chemistry] ,Biological Sciences ,Milk Proteins ,Medin ,Cerebrovascular Circulation ,Antigens, Surface ,Mfg-e8 ,Cerebrovascular Dysfunction ,Amyloid ,Mfge8 protein, mouse ,Female ,ddc:500 ,cerebrovascular dysfunction ,medicine.medical_specialty ,Population ,pathology [Aorta] ,MFG-E8 ,physiology [Cerebrovascular Circulation] ,genetics [Milk Proteins] ,genetics [Antigens, Surface] ,medicine.artery ,Internal medicine ,medicine ,Animals ,Humans ,metabolism [Aging] ,Vascular Diseases ,Healthy aging ,education ,metabolism [Amyloid] ,Brain Chemistry ,business.industry ,Upper body ,aging ,Wild type mice ,metabolism [Aorta] ,Mice, Inbred C57BL ,Endocrinology ,business ,pathology [Vascular Diseases] - Abstract
Significance Vascular dysfunction, as it develops either during normal aging or vascular disease, remains a major medical problem. The amyloid Medin, which is derived from its precursor protein MFG-E8 (through unknown mechanisms), forms insoluble aggregates in the vasculature of virtually anybody over 50 years of age, and it has been hypothesized that Medin aggregation could contribute to age-associated vascular decline; however, mechanistic analyses have so far been lacking. Our data now demonstrate that reminiscent of humans, mice also develop Medin deposits in an age-dependent manner. Importantly, mice that genetically lack Medin show reduced vascular dysfunction in the aged brain. Therefore, the prevention of Medin accumulation should be investigated as a novel therapeutic approach to preserve vascular health in the aging population.
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- 2020
11. Prominent microglial inclusions in transgenic mouse models of alpha-synucleinopathy that are distinct from neuronal lesions
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Ulrike Obermüller, Mathias Jucker, Deborah Kronenberg-Versteeg, Mehtap Bacioglu, Melanie Barth, Angelos Skodras, Jasmin Mahler, Gaye Tanriöver, Philipp J. Kahle, Yvonne S. Eisele, Manuel Schweighauser, Derya R. Shimshek, Bettina M. Wegenast-Braun, K. Peter R. Nilsson, Jucker, Mathias [0000-0001-9045-1072], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Synucleinopathies ,Protein Conformation ,Synuclein ,Microglia ,Inclusion ,Prion-like ,Amyloid ,Conformation ,Parkinsons disease ,lcsh:RC346-429 ,Mice ,0302 clinical medicine ,pathology [Inclusion Bodies] ,pathology [Neurons] ,metabolism [alpha-Synuclein] ,Inclusion Bodies ,Neurons ,Chemistry ,pathology [Microglia] ,genetics [Synucleinopathies] ,medicine.anatomical_structure ,genetics [alpha-Synuclein] ,alpha-Synuclein ,Phosphorylation ,Intracellular ,Neurovetenskaper ,Genetically modified mouse ,Cell type ,Transgene ,Mice, Transgenic ,Protein Aggregation, Pathological ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,pathology [Protein Aggregation, Pathological] ,metabolism [Protein Aggregation, Pathological] ,medicine ,genetics [Protein Aggregation, Pathological] ,Animals ,Humans ,ddc:610 ,lcsh:Neurology. Diseases of the nervous system ,Research ,Neurosciences ,Molecular biology ,Disease Models, Animal ,030104 developmental biology ,pathology [Synucleinopathies] ,chemistry [alpha-Synuclein] ,Parkinson’s disease ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated alpha-synuclein (alpha S). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of alpha S but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study alpha S conformers among different transgenic (TG) mouse models of alpha-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]alpha S; Thy1-h[A53T]alpha S; Thy1-h[A30P]alpha S; Thy1-m alpha S) that overexpress human or murine alpha S and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal alpha S pathology as evidenced by accumulation of alpha S serine 129 (p-alpha S) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study alpha S conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal alpha S pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of alpha S, but were largely p-alpha S-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded alpha S aggregation. Although nature and significance of microglial inclusions for human alpha-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of alpha-synucleinopathy bears importance for mechanistic and preclinical-translational studies. Funding Agencies|ECEuropean Commission Joint Research CentreEuropean Community (EC); EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking (IMPRiND) [116060]; Alexander von Humboldt-FoundationAlexander von Humboldt Foundation; German Academic Exchange Service (DAAD)Deutscher Akademischer Austausch Dienst (DAAD); Swedish Research CouncilSwedish Research Council [2016-00748]
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- 2020
12. Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life
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Paul H. Weinreb, Lary C. Walker, Matthias Staufenbiel, Ruth E. Uhlmann, Rawaa Al-Shaana, Emily M. Ullrich Gavilanes, Søren Christensen, Frank Baumann, Ulrike Obermüller, Stephan A. Kaeser, Fredrik Kartberg, Mathias Jucker, Angelos Skodras, Jay Rasmussen, Holger Cynis, Lan Ye, Anika Buehler, Fang Qian, Carina Bergmann, Juliane Schelle, Sarah K. Fritschi, Thierry Bussiere, Jens-Ulrich Rahfeld, Christine Rother, Natalie Beschorner, Jeffrey B. Stavenhagen, and Publica
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0301 basic medicine ,Male ,pharmacology [Tissue Extracts] ,pharmacokinetics [Antibodies, Monoclonal, Humanized] ,Plaque, Amyloid ,Protein aggregation ,pharmacology [Antibodies, Monoclonal, Humanized] ,neuroscience ,pathology [Alzheimer Disease] ,Amyloid beta-Protein Precursor ,Mice ,0302 clinical medicine ,Neurofilament Proteins ,antagonists & inhibitors [Amyloid beta-Protein Precursor] ,Aged, 80 and over ,biology ,Chemistry ,General Neuroscience ,aducanumab ,Middle Aged ,Alzheimer's disease ,Cell biology ,Aducanumab ,Antibody ,pharmacology [Antibodies, Blocking] ,metabolism [Alzheimer Disease] ,Genetically modified mouse ,Amyloid ,Immunoprecipitation ,Transgene ,metabolism [Amyloid beta-Peptides] ,Mice, Transgenic ,Antibodies, Monoclonal, Humanized ,Article ,03 medical and health sciences ,In vivo ,Alzheimer Disease ,Animals ,Humans ,ddc:610 ,pathology [Plaque, Amyloid] ,Antibodies, Blocking ,Aged ,Brain Chemistry ,Amyloid beta-Peptides ,Tissue Extracts ,cerebrospinal fluid [Neurofilament Proteins] ,Mice, Inbred C57BL ,030104 developmental biology ,biology.protein ,diseases of the nervous system ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer's disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease-currently defined as Aβ deposition without clinical symptoms-may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.
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- 2020
13. Early Aβ reduction prevents progression of cerebral amyloid angiopathy
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Nina Jährling, Angelos Skodras, Mathias Jucker, Bettina M. Wegenast-Braun, Stephan A. Kaeser, Daniel Eicke, Hans-Ulrich Dodt, Ulrike Obermueller, David P. Wolfer, Derya R. Shimshek, Thomas Mueggler, Matthias Staufenbiel, Sarah K. Fritschi, Juliane Schelle, Lisa M. Häsler, Natalie Beschorner, Ulf Neumann, University of Zurich, and Jucker, Mathias
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0301 basic medicine ,Pathology ,Neurology ,10017 Institute of Anatomy ,Thiazines ,antagonists & inhibitors [Amyloid Precursor Protein Secretases] ,cerebrospinal fluid [Amyloid beta-Peptides] ,Mice ,0302 clinical medicine ,Cerebrospinal fluid ,pharmacology [Thiazines] ,Amyloid precursor protein ,Aspartic Acid Endopeptidases ,Picolinic Acids ,biology ,Brain ,antagonists & inhibitors [Aspartic Acid Endopeptidases] ,Pathophysiology ,2728 Neurology (clinical) ,cerebrospinal fluid [Biomarkers] ,pharmacology [Picolinic Acids] ,Disease Progression ,Female ,Cerebral amyloid angiopathy ,Alzheimer's disease ,metabolism [Biomarkers] ,medicine.medical_specialty ,Amyloid ,Clinical Neurology ,metabolism [Amyloid beta-Peptides] ,Mice, Transgenic ,610 Medicine & health ,blood supply [Brain] ,03 medical and health sciences ,therapeutic use [Picolinic Acids] ,mental disorders ,medicine ,Animals ,Humans ,cardiovascular diseases ,ddc:610 ,cerebrospinal fluid [Peptide Fragments] ,therapeutic use [Thiazines] ,Amyloid beta-Peptides ,business.industry ,nutritional and metabolic diseases ,medicine.disease ,Peptide Fragments ,Cerebral Amyloid Angiopathy ,030104 developmental biology ,metabolism [Brain] ,2808 Neurology ,Hereditary cerebral hemorrhage with amyloidosis ,biology.protein ,drug therapy [Cerebral Amyloid Angiopathy] ,570 Life sciences ,Neurology (clinical) ,Amyloid Precursor Protein Secretases ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Objective Clinical trials targeting β-amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aβ deposition. Methods APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain. Results CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies. Interpretation This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.
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- 2019
14. Long-term adult human brain slice cultures as a model system to study human CNS circuitry and disease
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Harshad Pa, Yvonne G. Weber, Ulrike B. S. Hedrich, Betül Uysal, Albert J. Becker, Heidi Löffler, Niklas Schwarz, Angelos Skodras, Thomas V. Wuttke, Kornelijus Stanaitis, Jürgen Honegger, Jacqueline C Bahr, Marc Welzer, Henner Koch, and Nikolas Layer
- Subjects
0301 basic medicine ,Intravital Microscopy ,ved/biology.organism_classification_rank.species ,adult human neurons ,spines ,Disease ,physiopathology [Brain] ,chemistry.chemical_compound ,0302 clinical medicine ,pathology [Brain] ,morphology ,Biology (General) ,physiology [Pyramidal Cells] ,General Neuroscience ,Pyramidal Cells ,Brain ,General Medicine ,Human brain ,Tools and Resources ,medicine.anatomical_structure ,Cytoarchitecture ,pathology [Pyramidal Cells] ,Medicine ,Human ,Adult ,QH301-705.5 ,Science ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,physiology [Brain] ,methods [Organ Culture Techniques] ,Slice preparation ,Organ Culture Techniques ,Live cell imaging ,Biocytin ,medicine ,Humans ,Model organism ,General Immunology and Microbiology ,human brain slice cultures ,ved/biology ,methods [Intravital Microscopy] ,Electrophysiology ,030104 developmental biology ,chemistry ,ddc:600 ,anatomy & histology [Brain] ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Most of our knowledge on human CNS circuitry and related disorders originates from model organisms. How well such data translate to the human CNS remains largely to be determined. Human brain slice cultures derived from neurosurgical resections may offer novel avenues to approach this translational gap. We now demonstrate robust preservation of the complex neuronal cytoarchitecture and electrophysiological properties of human pyramidal neurons in long-term brain slice cultures. Further experiments delineate the optimal conditions for efficient viral transduction of cultures, enabling ‘high throughput’ fluorescence-mediated 3D reconstruction of genetically targeted neurons at comparable quality to state-of-the-art biocytin fillings, and demonstrate feasibility of long term live cell imaging of human cells in vitro. This model system has implications toward a broad spectrum of translational studies, regarding the validation of data obtained in non-human model systems, for therapeutic screening and genetic dissection of human CNS circuitry.
- Published
- 2019
15. Author response: Long-term adult human brain slice cultures as a model system to study human CNS circuitry and disease
- Author
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Marc Welzer, Yvonne G. Weber, Ulrike B. S. Hedrich, Albert J. Becker, Harshad Pa, Henner Koch, Angelos Skodras, Nikolas Layer, Jacqueline C Bahr, Thomas V. Wuttke, Heidi Löffler, Niklas Schwarz, Betül Uysal, Jürgen Honegger, and Kornelijus Stanaitis
- Subjects
medicine.anatomical_structure ,business.industry ,Medicine ,Model system ,Disease ,Human brain ,business ,Neuroscience ,Term (time) - Published
- 2019
16. Long-Term In Vivo Imaging of Individual Microglial Cells
- Author
-
Jasmin K Hefendehl, Angelos Skodras, Jonas J. Neher, Garaschuk, Olga, and Verkhratsky, Alexei
- Subjects
0301 basic medicine ,Microglia ,metabolism [Cerebral Cortex] ,Mice, Transgenic ,metabolism [Microglia] ,Biology ,cytology [Cerebral Cortex] ,Mice ,03 medical and health sciences ,Microscopy, Fluorescence, Multiphoton ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Cerebral cortex ,In vivo ,ddc:570 ,Parenchyma ,medicine ,Animals ,cytology [Microglia] ,Neuroscience ,030217 neurology & neurosurgery ,Preclinical imaging ,Cranial window - Abstract
Microglia are morphologically dynamic cells, neatly arranged in an interconnected three-dimensional lattice throughout the brain, constantly surveying the parenchyma, and swiftly responding to a variety of external stimuli. Capturing the dynamics of their morphology, reaction to trauma, pathogens, or endogenous stimuli, and studying changes in their network in their physiological environment requires the use of two-photon microscopy, as well as a precise repositioning strategy. Herein, we describe a robust repeatable localization method, coupled with optimized in vivo two-photon microscopy for long-term imaging of single microglia cells in the mouse brain.
- Published
- 2019
17. Conversion of Synthetic Aβ toIn VivoActive Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model
- Author
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Stephan A. Kaeser, Andreas Vlachos, Bettina M. Wegenast-Braun, Jonas J. Neher, Jasmin Mahler, Renata Novotny, Marie J. Pietrowski, Thomas Deller, Mathias Jucker, Matthias Staufenbiel, Yvonne S. Eisele, Franziska Langer, Bernd Heimrich, Angelos Skodras, and K. Peter R. Nilsson
- Subjects
Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Amyloid ,Hippocampal slice ,Transgene ,metabolism [Amyloid beta-Peptides] ,Plaque, Amyloid ,metabolism [Hippocampus] ,Mice, Transgenic ,Peptide ,Hippocampus ,Mice ,Amyloid beta-Protein Precursor ,03 medical and health sciences ,Organ Culture Techniques ,In vivo ,metabolism [Amyloid beta-Protein Precursor] ,Neurites ,medicine ,Animals ,pathology [Neurons] ,ddc:610 ,pathology [Plaque, Amyloid] ,Neurons ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Microglia ,General Neuroscience ,Neurodegeneration ,pathology [Microglia] ,Articles ,Amyloidosis ,medicine.disease ,metabolism [Plaque, Amyloid] ,In vitro ,Cell biology ,Mice, Inbred C57BL ,pathology [Hippocampus] ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Female ,pathology [Amyloidosis] ,pathology [Neurites] - Abstract
The aggregation of amyloid-β peptide (Aβ) in brain is an early event and hallmark of Alzheimer's disease (AD). We combined the advantages ofin vitroandin vivoapproaches to study cerebral β-amyloidosis by establishing a long-term hippocampal slice culture (HSC) model. While no Aβ deposition was noted in untreated HSCs of postnatal Aβ precursor protein transgenic (APP tg) mice, Aβ deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic Aβ. Seeded Aβ deposition was also observed under the same conditions in HSCs derived from wild-type orApp-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic Aβ species determined the conformational characteristics of HSC Aβ deposition. HSC Aβ deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast toin vitroaggregated synthetic Aβ, homogenates of Aβ deposits containing HSCs induced cerebral β-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic Aβ into a potentin vivoseeding-active form.SIGNIFICANCE STATEMENTIn this study, we report the seeded induction of Aβ aggregation and deposition in long-term hippocampal slice cultures. Remarkably, we find that the biological activities of the largely synthetic Aβ aggregates in the culture are very similar to those observedin vivo. This observation is the first to show that potentin vivoseeding-active Aβ aggregates can be obtained by seeded conversion of synthetic Aβ in a living (wild-type) cellular environment.
- Published
- 2016
18. Innate immune memory in the brain shapes neurological disease hallmarks
- Author
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Lalit Kaurani, Thomas Blank, Cemil Kerimoglu, Michael Gertig, Ori Staszewski, Jessica Wagner, Md. Rezaul Islam, Vincenzo Capece, Thomas Ulas, Matthias Staufenbiel, Andre Fischer, Mathias Jucker, Ann-Christin Wendeln, Katleen Wild, Marc Beyer, Jonas J. Neher, Tonatiuh Pena Centeno, Gaurav Jain, Joachim L. Schultze, Angelos Skodras, Karoline Degenhardt, Lisa M. Häsler, Marco Prinz, and Moumita Datta
- Subjects
0301 basic medicine ,Male ,animal diseases ,metabolism [Microglia] ,Immune tolerance ,Epigenesis, Genetic ,pathology [Alzheimer Disease] ,Mice ,immunology [Inflammation] ,pathology [Brain] ,immunology [Nervous System Diseases] ,Multidisciplinary ,Microglia ,Brain ,Amyloidosis ,immunology [Microglia] ,Stroke ,medicine.anatomical_structure ,immunology [Brain] ,Female ,ddc:500 ,pathology [Amyloidosis] ,medicine.symptom ,chemical and pharmacologic phenomena ,Inflammation ,Neuropathology ,Article ,03 medical and health sciences ,genetics [Inflammation] ,pathology [Nervous System Diseases] ,Immune system ,Immunity ,Alzheimer Disease ,medicine ,Immune Tolerance ,Animals ,Humans ,Innate immune system ,business.industry ,immunology [Gene Expression Regulation] ,biochemical phenomena, metabolism, and nutrition ,Immunity, Innate ,immunology [Amyloidosis] ,immunology [Alzheimer Disease] ,Disease Models, Animal ,030104 developmental biology ,Neuroimmunology ,Gene Expression Regulation ,pathology [Stroke] ,bacteria ,Nervous System Diseases ,business ,Neuroscience ,Immunologic Memory ,immunology [Stroke] - Abstract
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished—training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.
- Published
- 2018
19. Endogenous murine Aβ increases amyloid deposition in APP23 but not in APPPS1 transgenic mice
- Author
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Julia Stolz, Angelos Skodras, Paul M. Mathews, Carmen C. Duma, Harrison Wong, Yvonne S. Eisele, Rebecca Radde, Jose Morales-Corraliza, Mathias Jucker, William E. Klunk, Bettina M. Wegenast-Braun, K. Peter R. Nilsson, Matthias Staufenbiel, Matthew J. Mazzella, and Jasmin Mahler
- Subjects
Genetically modified mouse ,Aging ,BACE1-AS ,metabolism [Amyloid beta-Peptides] ,genetics [Alzheimer Disease] ,Mice, Transgenic ,Endogeny ,Peptide ,Article ,Amyloid beta-Protein Precursor ,Alzheimer Disease ,mental disorders ,Amyloid precursor protein ,medicine ,Animals ,Humans ,ddc:610 ,chemistry.chemical_classification ,Amyloid beta-Peptides ,biology ,General Neuroscience ,P3 peptide ,Brain ,medicine.disease ,Molecular biology ,Biochemistry of Alzheimer's disease ,Disease Models, Animal ,chemistry ,genetics [Amyloid beta-Protein Precursor] ,metabolism [Brain] ,biology.protein ,Neurology (clinical) ,Geriatrics and Gerontology ,Alzheimer's disease ,metabolism [Alzheimer Disease] ,Developmental Biology - Abstract
Endogenous murine amyloid-β peptide (Aβ) is expressed in most Aβ precursor protein (APP) transgenic mouse models of Alzheimer's disease but its contribution to β-amyloidosis remains unclear. We demonstrate ~35% increased cerebral Aβ load in APP23 transgenic mice compared to age-matched APP23 mice on an App-null background. No such difference was found for the much faster Aβ-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice co-deposited murine Aβ and immunoelectron microscopy revealed a tight association of murine Aβ with human Aβ fibrils. Deposition of murine Aβ was considerably less efficient compared to the deposition of human Aβ indicating a lower amyloidogenic potential of murine Aβ in vivo. The amyloid dyes Pittsburgh Compound B and pentamer formyl thiophene acetic acid (pFTAA 1) did not differentiate between amyloid deposits consisting of human Aβ and deposits of mixed human-murine Aβ. Our data demonstrate a differential effect of murine Aβ on human Aβ deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse Aβ may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies.
- Published
- 2015
20. Spine Loss in Primary Somatosensory Cortex during Trace Eyeblink Conditioning
- Author
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Angelos Skodras, Bettina Joachimsthaler, Dominik Brugger, and Cornelius Schwarz
- Subjects
Male ,Dendritic spine ,Dendritic Spines ,Neuroimaging ,Plasticity ,Somatosensory system ,Mice ,Physical Stimulation ,Animals ,ddc:610 ,Declarative learning ,physiology [Vibrissae] ,physiology [Conditioning, Eyelid] ,innervation [Vibrissae] ,physiology [Somatosensory Cortex] ,General Neuroscience ,Classical conditioning ,Somatosensory Cortex ,Articles ,Barrel cortex ,physiology [Dendritic Spines] ,Conditioning, Eyelid ,Mice, Inbred C57BL ,Spine (zoology) ,Eyeblink conditioning ,Vibrissae ,cytology [Somatosensory Cortex] ,Psychology ,Neuroscience - Abstract
Classical conditioning that involves mnemonic processing, that is, a “trace” period between conditioned and unconditioned stimulus, requires awareness of the association to be formed and is considered a simple model paradigm for declarative learning. Barrel cortex, the whisker representation of primary somatosensory cortex, is required for the learning of a tactile variant of trace eyeblink conditioning (TTEBC) and undergoes distinct map plasticity during learning. To investigate the cellular mechanism underpinning TTEBC and concurrent map plasticity, we used two-photon imaging of dendritic spines in barrel cortex of awake mice while being conditioned. Monitoring layer 5 neurons' apical dendrites in layer 1, we show that one cellular expression of barrel cortex plasticity is a substantial spine count reduction of ∼15% of the dendritic spines present before learning. The number of eliminated spines and their time of elimination are tightly related to the learning success. Moreover, spine plasticity is highly specific for the principal barrel column receiving the main signals from the stimulated vibrissa. Spines located in other columns, even those directly adjacent to the principal column, are unaffected. Because layer 1 spines integrate signals from associative thalamocortical circuits, their column-specific elimination suggests that this spine plasticity may be the result of an association of top-down signals relevant for declarative learning and spatially precise ascending tactile signals.
- Published
- 2015
21. Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging
- Author
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Robert Feil, Petra Füger, Bettina M. Wegenast-Braun, Peter Martus, Martin Thunemann, Jasmin K. Hefendehl, Christine Schlosser, Ulrike Obermüller, Angelos Skodras, Karthik Veeraraghavalu, Mathias Jucker, Jonas J. Neher, Sangram S. Sisodia, Shinichi Kohsaka, and Ann-Christin Wendeln
- Subjects
0301 basic medicine ,Senescence ,Programmed cell death ,Aging ,Transgene ,Cell ,Neocortex ,Plaque, Amyloid ,Mice, Transgenic ,Kaplan-Meier Estimate ,Biology ,physiopathology [Alzheimer Disease] ,03 medical and health sciences ,pathology [Alzheimer Disease] ,Mice ,0302 clinical medicine ,Single-cell analysis ,Alzheimer Disease ,ddc:570 ,medicine ,Animals ,cytology [Microglia] ,pathology [Plaque, Amyloid] ,physiology [Neocortex] ,Cell Proliferation ,Microglia ,Cell Death ,Cell growth ,General Neuroscience ,pathology [Microglia] ,physiology [Aging] ,physiology [Microglia] ,030104 developmental biology ,medicine.anatomical_structure ,Microscopy, Fluorescence, Multiphoton ,Single-Cell Analysis ,Neuroscience ,030217 neurology & neurosurgery ,Homeostasis - Abstract
To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimer's β-amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases.
- Published
- 2017
22. α‐Synuclein oligomers pump it up!
- Author
-
Angelos Skodras, Naoto Sugeno, and Philipp J. Kahle
- Subjects
metabolism [Parkinsonian Disorders] ,Excitotoxicity ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,ddc:570 ,medicine ,Humans ,metabolism [Sodium-Potassium-Exchanging ATPase] ,metabolism [alpha-Synuclein] ,Molecular Biology ,Alpha-synuclein ,General Immunology and Microbiology ,General Neuroscience ,Neurodegeneration ,medicine.disease ,chemistry ,Biochemistry ,metabolism [Hemiplegia] ,metabolism [Neurons] ,Mutation ,alpha-Synuclein ,Biophysics ,α synuclein ,Sodium-Potassium-Exchanging ATPase - Abstract
Oligomeric forms of the Parkinson9s disease‐causing protein α‐synuclein are suspected to mediate neurodegeneration, but the mechanisms are not understood. The present study of Shrivastava et al (2015) provides a fresh insight into this old mystery. α‐Synuclein oligomers are shown by a combination of top state‐of‐the‐art biochemical and super‐resolution microscopy methods to sequester the neuronal sodium–potassium pump. Such perturbation of ion currents would ultimately lead to Ca 2+ excitotoxicity.
- Published
- 2015
23. Homeostatic and injury-induced microglia behavior in the aging brain
- Author
-
Shinichi Kohsaka, Jasmin K. Hefendehl, Mathias Jucker, Angelos Skodras, Jonas J. Neher, and Rafael Barbizan Sühs
- Subjects
Aging ,Pathology ,medicine.medical_specialty ,Population ,microglia ,Poison control ,Biology ,Mice ,pathology [Aging] ,Imaging, Three-Dimensional ,pathology [Brain] ,Cell Movement ,neocortex ,medicine ,Animals ,Homeostasis ,Aging brain ,ddc:610 ,Cognitive decline ,education ,Cell Shape ,education.field_of_study ,Neocortex ,Microglia ,pathology [Brain Injuries] ,Lasers ,Neurodegeneration ,neurodegeneration ,Brain ,pathology [Microglia] ,Original Articles ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,medicine.anatomical_structure ,nervous system ,Brain Injuries ,in vivo imaging ,Neuroscience - Abstract
Microglia cells are essential for brain homeostasis and have essential roles in neurodegenerative diseases. Aging is the main risk factor for most neurodegenerative diseases and age-related changes in microglia may contribute to the susceptibility of the aging brain to dysfunction and neurodegeneration. We have analyzed morphology and dynamic behavior of neocortical microglia in their physiological environment in young adult (3 mo-old), adult (11-12 mo-old) and aged (26-27 mo-old) C57BL/6J-Iba1-eGFP mice using in vivo 2-photon microscopy. Results show that surveying microglial cells in the neocortex exhibit age-related soma volume increase, shortening of processes, and loss of homogeneous tissue distribution. Furthermore, microglial process speed significantly decreased with age. While only a small population of microglia showed soma movement in adult mice, the microglia population with soma movement was increased in aged mice. However, in response to tissue injury the dynamic microglial response was age- dependently diminished. These results provide novel insights into microglial behavior and indicate that microglial dysfunction in the aging brain may contribute to age-related cognitive decline and neurodegenerative diseases. This article is protected by copyright. All rights reserved. Language: en
- Published
- 2013
24. Spectral Discrimination of Cerebral Amyloid Lesions after Peripheral Application of Luminescent Conjugated Oligothiophenes
- Author
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Mathias Jucker, K. Peter R. Nilsson, Bettina M. Wegenast-Braun, Gonca Bayraktar, Christian Liebig, Sarah K. Fritschi, Per Hammarström, Angelos Skodras, Jasmin Mahler, Therése Klingstedt, and Jeffrey J. Mason
- Subjects
Pathology ,medicine.medical_specialty ,Amyloid ,Luminescence ,Tau protein ,Mice, Transgenic ,Thiophenes ,Protein aggregation ,Pathology and Forensic Medicine ,03 medical and health sciences ,pathology [Alzheimer Disease] ,Mice ,0302 clinical medicine ,methods [Microscopy, Fluorescence, Multiphoton] ,chemistry [Thiophenes] ,In vivo ,Alzheimer Disease ,pathology [Brain] ,administration & dosage [Thiophenes] ,mental disorders ,medicine ,Animals ,Humans ,Senile plaques ,ddc:610 ,030304 developmental biology ,metabolism [Amyloid] ,0303 health sciences ,biology ,Staining and Labeling ,Chemistry ,P3 peptide ,Brain ,pathology [Blood-Brain Barrier] ,medicine.disease ,Immunohistochemistry ,3. Good health ,Biochemistry of Alzheimer's disease ,Mice, Inbred C57BL ,Microscopy, Fluorescence, Multiphoton ,Blood-Brain Barrier ,metabolism [Brain] ,biology.protein ,Biophysics ,Alzheimer's disease ,metabolism [Blood-Brain Barrier] ,030217 neurology & neurosurgery ,Ex vivo ,metabolism [Alzheimer Disease] - Abstract
In vivo imaging of pathological protein aggregates provides essential knowledge of the kinetics and implications of these lesions in the progression of proteopathies, such as Alzheimer disease. Luminescent conjugated oligothiophenes are amyloid-specific ligands that bind and spectrally distinguish different types of amyloid aggregates. Herein, we report that heptamer formyl thiophene acetic acid (hFTAA) passes the blood-brain barrier after systemic administration and specifically binds to extracellular β-amyloid deposits in the brain parenchyma (Aβ plaques) and in the vasculature (cerebral β-amyloid angiopathy) of β-amyloid precursor protein transgenic APP23 mice. Moreover, peripheral application of hFTAA also stained intracellular lesions of hyperphosphorylated Tau protein in P301S Tau transgenic mice. Spectral profiling of all three amyloid types was acquired ex vivo using two-photon excitation. hFTAA revealed a distinct shift in its emission spectra when bound to Aβ plaques versus Tau lesions. Furthermore, a spectral shift was observed for Aβ plaques versus cerebral β-amyloid angiopathy, indicating that different amyloid types and structural variances of a specific amyloid type can be distinguished. In conclusion, by adding spectral signatures to amyloid lesions, our results pave the way for a new area of in vivo amyloid imaging, allowing in vivo differentiation of amyloid (sub)types and monitoring changes of their structure/composition over time.
- Published
- 2012
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25. Parenchymal cystatin C focal deposits and glial scar formation around brain arteries in Hereditary Cystatin C Amyloid Angiopathy
- Author
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Birkir Thor Bragason, Stephan A. Kaeser, Elias Olafsson, Helgi J Isaksson, Angelos Skodras, Astridur Palsdottir, and Asbjorg Osk Snorradottir
- Subjects
Male ,Pathology ,metabolism [Antigens, CD] ,Cerebral arteries ,metabolism [Arterioles] ,pathology [Arterioles] ,CD68 antigen, human ,pathology [Brain] ,genetics [Cerebral Amyloid Angiopathy, Familial] ,metabolism [Cicatrix] ,AIF1 protein, human ,Glial fibrillary acidic protein ,biology ,General Neuroscience ,Microfilament Proteins ,Brain ,Anatomy ,Middle Aged ,genetics [Cystatin C] ,DNA-Binding Proteins ,Arterioles ,CST3 protein, human ,medicine.anatomical_structure ,Female ,metabolism [DNA-Binding Proteins] ,Neuroglia ,Brain Infarction ,Adult ,pathology [Cicatrix] ,medicine.medical_specialty ,Amyloid ,Neuroimmunomodulation ,physiology [Neuroimmunomodulation] ,Antigens, Differentiation, Myelomonocytic ,physiopathology [Cerebral Amyloid Angiopathy, Familial] ,Glial scar ,White matter ,blood supply [Brain] ,Cicatrix ,Young Adult ,physiopathology [Brain Infarction] ,Antigens, CD ,Parenchyma ,Glial Fibrillary Acidic Protein ,medicine ,Humans ,pathology [Cerebral Arteries] ,ddc:610 ,Cystatin C ,Molecular Biology ,Aged ,pathology [Neuroglia] ,Calcium-Binding Proteins ,pathology [Brain Infarction] ,metabolism [Glial Fibrillary Acidic Protein] ,pathology [Cerebral Amyloid Angiopathy, Familial] ,Cerebral Arteries ,Hereditary cystatin C amyloid angiopathy ,metabolism [Antigens, Differentiation, Myelomonocytic] ,metabolism [Brain] ,biology.protein ,metabolism [Cystatin C] ,Neurology (clinical) ,Developmental Biology ,Cerebral Amyloid Angiopathy, Familial - Abstract
Hereditary Cystatin C Amyloid Angiopathy (HCCAA) is an amyloid disorder in Icelandic families caused by an autosomal dominant mutation in the cystatin C gene. Mutant cystatin C forms amyloid deposits in brain arteries and arterioles which are associated with changes in the arterial wall structure, notably deposition of extracellular matrix proteins. In this post-mortem study we examined the neuroinflammatory response relative to the topographical distribution of cystatin C deposition, and associated haemorrhages, in the leptomeninges, cerebrum, cerebellum, thalamus, and midbrain of HCCAA patients. Cystatin C was deposited in all brain areas, grey and white matter alike, most prominently in arteries and arterioles; capillaries and veins were not, or minimally, affected. We also observed perivascular deposits and parenchymal focal deposits proximal to affected arteries. This study shows for the first time, that cystatin C does not exclusively form CAA and perivascular amyloid but also focal deposits in the brain parenchyma. Haemorrhages were observed in all patients and occurred in all brain areas, variable between patients. Microinfarcts were observed in 34.6% of patients. The neuroinflammatory response was limited to the close vicinity of affected arteries and perivascular as well as parenchymal focal deposits. Taken together with previously reported arterial accumulation of extracellular matrix proteins in HCCAA, our results indicate that the central nervous system pathology of HCCAA is characterised by the formation of a glial scar within and around affected arteries.
- Published
- 2015
26. Computer-generated ovaries to assist follicle counting experiments
- Author
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Angelos Skodras and Gianluca Marcelli
- Subjects
medicine.medical_specialty ,Specific time ,lcsh:Medicine ,Ovary ,Cell Count ,Biology ,Statistical power ,cytology [Ovarian Follicle] ,Follicle ,Mice ,Ovarian Follicle ,Internal medicine ,Reproductive biology ,medicine ,Animals ,Computer Simulation ,ddc:610 ,Reproductive system ,Ovarian follicle ,lcsh:Science ,cytology [Ovary] ,Multidisciplinary ,lcsh:R ,Neonatal mouse ,medicine.anatomical_structure ,Endocrinology ,lcsh:Q ,Female ,Biological system ,Algorithms ,Research Article - Abstract
Precise estimation of the number of follicles in ovaries is of key importance in the field of reproductive biology, both from a developmental point of view, where follicle numbers are determined at specific time points, as well as from a therapeutic perspective, determining the adverse effects of environmental toxins and cancer chemotherapeutics on the reproductive system. The two main factors affecting follicle number estimates are the sampling method and the variation in follicle numbers within animals of the same strain, due to biological variability. This study aims at assessing the effect of these two factors, when estimating ovarian follicle numbers of neonatal mice. We developed computer algorithms, which generate models of neonatal mouse ovaries (simulated ovaries), with characteristics derived from experimental measurements already available in the published literature. The simulated ovaries are used to reproduce in-silico counting experiments based on unbiased stereological techniques; the proposed approach provides the necessary number of ovaries and sampling frequency to be used in the experiments given a specific biological variability and a desirable degree of accuracy. The simulated ovary is a novel, versatile tool which can be used in the planning phase of experiments to estimate the expected number of animals and workload, ensuring appropriate statistical power of the resulting measurements. Moreover, the idea of the simulated ovary can be applied to other organs made up of large numbers of individual functional units.
- Published
- 2014
27. Multiple factors contribute to the peripheral induction of cerebral beta-amyloidosis
- Author
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Petra Füger, Angelos Skodras, Tsuyoshi Hamaguchi, Ulrike Obermüller, Claudia Schäfer, Yvonne S. Eisele, Mathias Jucker, Sarah K. Fritschi, Matthias Staufenbiel, Mathias Heikenwalder, and Jörg Odenthal
- Subjects
Male ,Pathology ,Time Factors ,pharmacology [Antibodies] ,metabolism [Blood Cells] ,Peptide ,Plaque, Amyloid ,drug effects [Cerebral Cortex] ,Mice ,Amyloid beta-Protein Precursor ,Peritoneal Cavity ,chemistry.chemical_classification ,Cerebral Cortex ,chemically induced [Amyloidosis] ,biology ,Chemistry ,General Neuroscience ,Amyloidosis ,Drug Administration Routes ,Articles ,pathology [Peritoneal Cavity] ,immunology [Amyloid beta-Peptides] ,medicine.anatomical_structure ,genetics [Amyloid beta-Protein Precursor] ,pathology [Blood Cells] ,Female ,pathology [Amyloidosis] ,Antibody ,Genetically modified mouse ,medicine.medical_specialty ,genetics [Amyloidosis] ,Transgene ,metabolism [Amyloid beta-Peptides] ,Spleen ,Mice, Transgenic ,genetics [Mutation] ,Antibodies ,Angiopathy ,mental disorders ,medicine ,Animals ,Humans ,ddc:610 ,pathology [Plaque, Amyloid] ,Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12] ,Beta (finance) ,Blood Cells ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,metabolism [Cerebral Cortex] ,medicine.disease ,Molecular biology ,toxicity [Amyloid beta-Peptides] ,nervous system diseases ,Mice, Inbred C57BL ,Mutation ,biology.protein ,pathology [Cerebral Cortex] ,Abeta ,Cerebral Beta-amyloidosis ,Peripheral Induction ,Seeding - Abstract
Contains fulltext : 135971.pdf (Publisher’s version ) (Open Access) Deposition of aggregated amyloid-beta (Abeta) peptide in brain is an early event and hallmark pathology of Alzheimer's disease and cerebral Abeta angiopathy. Experimental evidence supports the concept that Abeta multimers can act as seeds and structurally corrupt other Abeta peptides by a self-propagating mechanism. Here we compare the induction of cerebral beta-amyloidosis by intraperitoneal applications of Abeta-containing brain extracts in three Abeta-precursor protein (APP) transgenic mouse lines that differ in levels of transgene expression in brain and periphery (APP23 mice, APP23 mice lacking murine APP, and R1.40 mice). Results revealed that beta-amyloidosis induction, which could be blocked with an anti-Abeta antibody, was dependent on the amount of inoculated brain extract and on the level of APP/Abeta expression in the brain but not in the periphery. The induced Abeta deposits in brain occurred in a characteristic pattern consistent with the entry of Abeta seeds at multiple brain locations. Intraperitoneally injected Abeta could be detected in blood monocytes and some peripheral tissues (liver, spleen) up to 30 d after the injection but escaped histological and biochemical detection thereafter. These results suggest that intraperitoneally inoculated Abeta seeds are transported from the periphery to the brain in which corruptive templating of host Abeta occurs at multiple sites, most efficiently in regions with high availability of soluble Abeta.
- Published
- 2014
28. Deposition of collagen IV and aggrecan in leptomeningeal arteries of hereditary brain haemorrhage with amyloidosis
- Author
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Stephan A. Kaeser, Astridur Palsdottir, Birkir Thor Bragason, Helgi J Isaksson, Angelos Skodras, Elias Olafsson, and Asbjorg Osk Snorradottir
- Subjects
Adult ,Male ,Collagen Type IV ,Pathology ,medicine.medical_specialty ,genetics [Amyloidosis] ,genetics [Cerebral Hemorrhage] ,Amyloid ,Cerebral arteries ,metabolism [Collagen Type IV] ,metabolism [Aggrecans] ,Laminin ,pathology [Brain] ,medicine ,Humans ,ddc:610 ,Aggrecans ,Cystatin C ,Molecular Biology ,Aggrecan ,metabolism [Cerebral Hemorrhage] ,Cerebral Hemorrhage ,Aged ,Aged, 80 and over ,metabolism [Amyloidosis] ,biology ,pathology [Cerebral Hemorrhage] ,business.industry ,General Neuroscience ,Amyloidosis ,Brain ,Middle Aged ,Hereditary cystatin C amyloid angiopathy ,medicine.disease ,genetics [Cystatin C] ,metabolism [Brain] ,Mutation ,biology.protein ,metabolism [Cystatin C] ,Female ,Neurology (clinical) ,Cerebral amyloid angiopathy ,pathology [Amyloidosis] ,business ,Developmental Biology - Abstract
Hereditary Cystatin C Amyloid Angiopathy (HCCAA) is a rare genetic disease in Icelandic families caused by a mutation in the cystatin C gene, CST3. HCCAA is classified as a cerebral amyloid angiopathy and mutant cystatin C forms amyloid deposits in cerebral arteries resulting in fatal haemorrhagic strokes in young adults. The aetiology of HCCAA pathology is not clear and there is, at present, no animal model of the disease. The aim of this study was to increase understanding of the cerebral vascular pathology of HCCAA patients with an emphasis on structural changes within the arterial wall of affected leptomeningeal arteries. Examination of post-mortem samples revealed extensive changes in the walls of affected arteries characterised by deposition of extracellular matrix constituents, notably collagen IV and the proteoglycan aggrecan. Other structural abnormalities were thickening of the laminin distribution, intimal thickening concomitant with a frayed elastic layer, and variable reduction in the integrity of endothelia. Our results show that excess deposition of extracellular matrix proteins in cerebral arteries of HCCAA is a prominent feature of the disease and may play an important role in its pathogenesis.
- Published
- 2013
29. Object recognition in the ovary: Quantification of oocytes from microscopic images
- Author
-
Jaroslav Stark, Stamatia Giannarou, Kate Hardy, Angelos Skodras, Stephen Franks, and Mark A. Fenwick
- Subjects
Microscope ,Absolute number ,business.industry ,Cognitive neuroscience of visual object recognition ,Ovary ,Biology ,Oocyte ,Cell biology ,law.invention ,medicine.anatomical_structure ,Rician channels ,law ,medicine ,Computer vision ,Artificial intelligence ,business ,Microscope image processing ,Cellular biophysics - Abstract
The ovary is a female organ that houses a fixed supply of germ cells (oocytes). The absolute number of oocytes at any given stage can be a useful indicator of fertility. Obtaining accurate assessments of the oocyte reserve in humans and experimental models can be time consuming and error prone. In this paper a new approach to facilitate oocyte counting in microscope images of mouse ovaries is presented. The mouse vasa homolog (MVH), an oocyte-specific protein, was labeled in microscope sections and used to develop an algorithm that can identify, count and estimate the size and coordinates of the oocytes. We use this automated approach to generate comparable data with conventional methods of oocyte counting.
- Published
- 2009
30. Compression of confocal microscopy images: a comparative study
- Author
-
Athanassios N. Skodras and Angelos Skodras
- Subjects
Lossless compression ,Computer science ,business.industry ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,Image processing ,Data_CODINGANDINFORMATIONTHEORY ,computer.file_format ,Lossy compression ,JPEG ,Compression (functional analysis) ,JPEG 2000 ,Computer vision ,Artificial intelligence ,business ,computer ,Image compression ,Data compression - Abstract
In the present communication an extensive study of lossless and lossy compression of laser confocal microscopy images is conducted. For the lossy (irreversible) case, both objective and subjective results are given. It is shown that the JPEG2000 compression standard outperforms all others, even the recently introduced HD Photo, in both the reversible and irreversible cases. More specifically, the JPEG2000 lossless performance is approximately 15% better than the next best image data compression algorithm tested (namely the PNG) and the JPEG2000 lossy compression objective performance results are at least 3dB better than that of HD Photo or JPEG.
- Published
- 2008
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