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1. Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer’s disease

Author

Hofmann, Anna, Häsler, Lisa M., Lambert, Marius, Kaeser, Stephan A., Gräber-Sultan, Susanne, Obermüller, Ulrike, Kuder-Buletta, Elke, la Fougere, Christian, Laske, Christoph, Vöglein, Jonathan, Levin, Johannes, Fox, Nick C., Ryan, Natalie S., Zetterberg, Henrik, Llibre-Guerra, Jorge J., Perrin, Richard J., Ibanez, Laura, Schofield, Peter R., Brooks, William S., Day, Gregory S., Farlow, Martin R., Allegri, Ricardo F., Chrem Mendez, Patricio, Ikeuchi, Takeshi, Kasuga, Kensaku, Lee, Jae-Hong, Roh, Jee Hoon, Mori, Hiroshi, Lopera, Francisco, Bateman, Randall J., McDade, Eric, Gordon, Brian A., Chhatwal, Jasmeer P., Jucker, Mathias, and Schultz, Stephanie A.

Published
2024
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2. Serum IL-6, sAXL, and YKL-40 as systemic correlates of reduced brain structure and function in Alzheimer’s disease: results from the DELCODE study

Author

Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, Kolbe, Carl-Christian, Wolfsgruber, Steffen, Santarelli, Francesco, Häsler, Lisa M., McManus, Róisín, Ising, Christina, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Schneider, Luisa-Sophie, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Buerger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Görß, Doreen, Laske, Christoph, Munk, Matthias H., Düzel, Emrah, Yakupow, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Spottke, Annika, Ramirez, Alfredo, Mengel, David, Synofzik, Matthis, Jucker, Mathias, Latz, Eicke, Jessen, Frank, Wagner, Michael, and Heneka, Michael T.

Published
2023
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3. Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Author

Wagner, Jessica, Degenhardt, Karoline, Veit, Marleen, Louros, Nikolaos, Konstantoulea, Katerina, Skodras, Angelos, Wild, Katleen, Liu, Ping, Obermüller, Ulrike, Bansal, Vikas, Dalmia, Anupriya, Häsler, Lisa M., Lambert, Marius, De Vleeschouwer, Matthias, Davies, Hannah A., Madine, Jillian, Kronenberg-Versteeg, Deborah, Feederle, Regina, Del Turco, Domenico, Nilsson, K. Peter R., Lashley, Tammaryn, Deller, Thomas, Gearing, Marla, Walker, Lary C., Heutink, Peter, Rousseau, Frederic, Schymkowitz, Joost, Jucker, Mathias, and Neher, Jonas J.

Published
2022
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4. Soluble TAM receptors sAXL and sTyro3 predict structural and functional protection in Alzheimer’s disease

Author

Brosseron, Frederic, Maass, Anne, Kleineidam, Luca, Ravichandran, Kishore Aravind, González, Pablo García, McManus, Róisín M., Ising, Christina, Santarelli, Francesco, Kolbe, Carl-Christian, Häsler, Lisa M., Wolfsgruber, Steffen, Marquié, Marta, Boada, Mercè, Orellana, Adelina, de Rojas, Itziar, Röske, Sandra, Peters, Oliver, Cosma, Nicoleta-Carmen, Cetindag, Arda, Wang, Xiao, Priller, Josef, Spruth, Eike J., Altenstein, Slawek, Schneider, Anja, Fliessbach, Klaus, Wiltfang, Jens, Schott, Björn H., Bürger, Katharina, Janowitz, Daniel, Dichgans, Martin, Perneczky, Robert, Rauchmann, Boris-Stephan, Teipel, Stefan, Kilimann, Ingo, Goerss, Doreen, Laske, Christoph, Munk, Matthias H., Düzel, Emrah, Yakupov, Renat, Dobisch, Laura, Metzger, Coraline D., Glanz, Wenzel, Ewers, Michael, Dechent, Peter, Haynes, John Dylan, Scheffler, Klaus, Roy, Nina, Rostamzadeh, Ayda, Teunissen, Charlotte E., Marchant, Natalie L., Spottke, Annika, Jucker, Mathias, Latz, Eicke, Wagner, Michael, Mengel, David, Synofzik, Matthis, Jessen, Frank, Ramirez, Alfredo, Ruiz, Agustín, and Heneka, Michael T.

Published
2022
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5. Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Author

Rother, Christine, Uhlmann, Ruth E., Müller, Stephan A., Schelle, Juliane, Skodras, Angelos, Obermüller, Ulrike, Häsler, Lisa M., Lambert, Marius, Baumann, Frank, Xu, Ying, Bergmann, Carina, Salvadori, Giulia, Loos, Maarten, Brzak, Irena, Shimshek, Derya, Neumann, Ulf, Walker, Lary C., Schultz, Stephanie A., Chhatwal, Jasmeer P., Kaeser, Stephan A., Lichtenthaler, Stefan F., Staufenbiel, Matthias, and Jucker, Mathias

Published
2022
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9. Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Author

Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa M., Schweighauser, Manuel, Wuttke, Thomas V., Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp J., Shimshek, Derya R., Koch, Henner, Jucker, Mathias, and Tanriöver, Gaye

Published
2021
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10. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease

Author

Rasmussen, Jay, Mahler, Jasmin, Beschorner, Natalie, Kaeser, Stephan A., Häsler, Lisa M., Baumann, Frank, Nyström, Sofie, Portelius, Erik, Blennow, Kaj, Lashley, Tammaryn, Fox, Nick C., Sepulveda-Falla, Diego, Glatzel, Markus, Oblak, Adrian L., Ghetti, Bernardino, Nilsson, K. Peter R., Hammarström, Per, Staufenbiel, Matthias, Walker, Lary C., and Jucker, Mathias

Published
2017

12. Innate immune memory in the brain shapes neurological disease hallmarks

Author

Wendeln, Ann-Christin, Degenhardt, Karoline, Kaurani, Lalit, Gertig, Michael, Ulas, Thomas, Jain, Gaurav, Wagner, Jessica, Häsler, Lisa M., Wild, Katleen, Skodras, Angelos, Blank, Thomas, Staszewski, Ori, Datta, Moumita, Centeno, Tonatiuh Pena, Capece, Vincenzo, Islam, Md. Rezaul, Kerimoglu, Cemil, Staufenbiel, Matthias, Schultze, Joachim L., Beyer, Marc, Prinz, Marco, Jucker, Mathias, Fischer, André, and Neher, Jonas J.

Published
2018
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14. LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies

Author

Emmenegger, Marc, De Cecco, Elena, Hruska-Plochan, Marian, Eninger, Timo, Schneider, Matthias M, Barth, Melanie, Tantardini, Elena, De Rossi, Pierre, Bacioglu, Mehtap, Langston, Rebekah G, Kaganovich, Alice, Bengoa-Vergniory, Nora, Gonzalez-Guerra, Andrès, Avar, Merve, Heinzer, Daniel, Reimann, Regina, Häsler, Lisa M, Herling, Therese W, Matharu, Naunehal S, Landeck, Natalie, Luk, Kelvin, Melki, Ronald, Kahle, Philipp J, Hornemann, Simone, Knowles, Tuomas PJ, Cookson, Mark R, Polymenidou, Magdalini, Jucker, Mathias, Aguzzi, Adriano, Universität Zürich [Zürich] = University of Zurich (UZH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Cambridge [UK] (CAM), National Institutes of Health [Bethesda] (NIH), University of Oxford [Oxford], Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Tübingen, National Centre for Competence in Research (NCCR) RNA & Disease (51NF40-182880), European Project: 670958,H2020,ERC-2014-ADG,PRION2020(2015), European Project: 674979,H2020,H2020-MSCA-ITN-2015,NANOTRANS(2016), European Project: (grant No 116060),IMPRiND, University of Oxford, Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Emmenegger, Marc [0000-0002-6073-8811], De Cecco, Elena [0000-0002-0148-2596], Hruska-Plochan, Marian [0000-0002-9253-4362], Schneider, Matthias M [0000-0002-1894-1859], Tantardini, Elena [0000-0001-9189-3390], Bacioglu, Mehtap [0000-0003-0304-7026], Bengoa-Vergniory, Nora [0000-0002-3700-0464], Avar, Merve [0000-0003-4665-5558], Heinzer, Daniel [0000-0002-3282-4042], Landeck, Natalie [0000-0002-8399-4009], Luk, Kelvin [0000-0002-6591-6269], Melki, Ronald [0000-0003-0000-7096], Hornemann, Simone [0000-0002-2674-9891], Cookson, Mark R [0000-0002-1058-3831], Jucker, Mathias [0000-0001-9045-1072], Aguzzi, Adriano [0000-0002-0344-6708], Apollo - University of Cambridge Repository, Hruska‐Plochan, Marian [0000-0002-9253-4362], Bengoa‐Vergniory, Nora [0000-0002-3700-0464], University of Zurich, and Aguzzi, Adriano

Subjects
Medicine (General), prionoids, Synucleinopathies, 10208 Institute of Neuropathology, 610 Medicine & health, Mice, Transgenic, QH426-470, Article, Mice, R5-920, α-synuclein, Genetics, Animals, Humans, ddc:610, Neurons, α‐synuclein, neurodegeneration, Parkinson Disease, Articles, nervous system diseases, EMBO27, 1313 Molecular Medicine, genetics [alpha-Synuclein], alpha-Synuclein, 570 Life sciences, biology, Molecular Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 11493 Department of Quantitative Biomedicine, Neuroscience, LAG3
Abstract

Funder: University of Zurich and University Hospital of Zurich, Funder: NOMIS Stiftung (NOMIS Foundation); Id: http://dx.doi.org/10.13039/501100008483, Funder: Forschungskredit University of Zurich, While the initial pathology of Parkinson’s disease and other α‐synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α‐synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α‐synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α‐synuclein pathology ex vivo. The overall survival of A53T α‐synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α‐synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α‐synucleinopathies is not universally valid.

Published
2021
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15. Additional file 1 of Cerebrospinal fluid cytokine levels are associated with macrophage infiltration into tumor tissues of glioma patients

Author

Kemmerer, Constanze L., Schittenhelm, Jens, Dubois, Evelyn, Neumann, Laura, Häsler, Lisa M., Lambert, Marius, Renovanz, Mirjam, Kaeser, Stephan A., Tabatabai, Ghazaleh, Ziemann, Ulf, Naumann, Ulrike, and Kowarik, Markus C.

Abstract

Additional file 1: Table S1. Data Cleaning. Table S2. Correlations between cytokines and inflammatory cell infiltrates in the tumor core. Table S3. Correlations between cytokines and inflammatory cell infiltrates in the perivascular area.

Published
2021
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16. Additional file 4 of Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Author

Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa M., Schweighauser, Manuel, Wuttke, Thomas V., Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp J., Shimshek, Derya R., Koch, Henner, Jucker, Mathias, and Tanriöver, Gaye

Abstract

Additional file 4: Supplementary Fig. 4. Time course of seeded αS aggregation in Thy1-h[A53T]αS tg mice. (A, B) Immunohistochemistry for pS129 (black) of DG from Thy1-h[A53T]αS tg mice injected at 3–4 months of age with Thy1-h[A53T]αS tg brain homogenate (A) or wt brain homogenate (B) at one day post-injection (dpi), 7 dpi or 30 dpi. For each group, three mice were used. Sections were counter stained using nuclear fast red. Note that the same brain homogenates were used for slice culture experiments. (A) First inclusions appeared around 7 dpi in all three mice and became more abundant by 30 dpi. (B) In contrast, no inclusions were found in wt brain homogenate-treated mice at any time point analysed. Scale bar represents 100 μm.

Published
2021
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17. Additional file 1 of Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Author

Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa M., Schweighauser, Manuel, Wuttke, Thomas V., Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp J., Shimshek, Derya R., Koch, Henner, Jucker, Mathias, and Tanriöver, Gaye

Abstract

Additional file 1: Supplementary Fig. 1. αS pff characterization. (A, B) Proteolytic profiles of monomeric (A) and fibrillar (B) αS (100 M in PBS) after proteinase K treatment (3.7 μg/μl) at 37 °C. Aliquots were removed from the reaction at the time indicated (in min), immediately denatured with Laemmli buffer at 90 °C for 5 min and analysed on 15% PAGE. The gels were stained with Coomassie blue. The molecular weight markers are shown on the left of each gel. The αS fibrils reveal the typical proteolytic pattern as reported previously [30, 31]. (C, D) Transmission electron micrographs of the αS fibrils before (C) and after fragmentation (D). The scale bar represents 200 nm.

Published
2021
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18. Additional file 5 of Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Author

Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa M., Schweighauser, Manuel, Wuttke, Thomas V., Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp J., Shimshek, Derya R., Koch, Henner, Jucker, Mathias, and Tanriöver, Gaye

Abstract

Additional file 5: Supplementary Fig. 5. Treatment with highly concentrated αS pff is neurotoxic to Thy1-h[A53T]αS tg HSCs. (A) Immunostaining of pS129-positive aggregates in 50 μm-horizontal sections from Thy1-h[A53T]αS tg HSCs treated with 350 μM αS pff at 1, 2 and 5 weeks post-seeding. Scale bar = 500 μm. (B) Measurement of culture thickness (in μm at the time of fixation) in untreated, 350 μM αS pff-treated and 35 μM αS pff-treated tg HSCs. Mean ± SEM; n(untr., 1 week) = 6, n(untr., 3 weeks) = 18, n(untr., 5 weeks) = 19, n(35 μM pff, 1 week) = 15, n(35 μM pff, 2 weeks) = 10, n(35 μM pff, 3 weeks) = 31, n(35 μM pff, 4 weeks) = 9, n(35 μM pff, 5 weeks) = 18, n(350 μM pff, 1–4 weeks) = 6 each, n(350 μM pff, 5 weeks) = 35 HSCs per group. Note that culture thickness was routinely measured and results come from many different experiments, which accounts for the differences among the n/group. (C) Violin graphs displaying thickness of tg HSCs across different treatments at 5 weeks post-treatment. n(tg, untr.) = 19, n(tg, tg brain hom.) = 24, n(tg, 35 μM pff) = 18, n(tg, 350 μM pff) = 35. Kruskal-Wallis test (H = 45.82; p

Published
2021
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19. Additional file 2 of Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Author

Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa M., Schweighauser, Manuel, Wuttke, Thomas V., Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp J., Shimshek, Derya R., Koch, Henner, Jucker, Mathias, and Tanriöver, Gaye

Abstract

Additional file 2: Supplementary Fig. 2 Induction of αS aggregation is dependent on endogenous αS expression. Immunofluorescence staining for pS129 showed inclusions in Thy1-h[A53T]αS tg HSCs seeded with Thy1-h[A53T]αS tg brain homogenate. In contrast, there was no induction of αS aggregation in Snca−/− HSCs after seeding using the same brain homogenate as seed. Analysis was done 5 weeks after treatment. See Fig. 1 for methodological detail. The experiment was done twice with 3 cultures each. Scale bar = 500 μm.

Published
2021
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20. Author Reply to Peer Reviews of LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies

Author

Aguzzi, Adriano, primary, Jucker, Mathias, additional, Polymenidou, Magdalini, additional, Cookson, Mark R., additional, Knowles, Tuomas P. J., additional, Hornemann, Simone, additional, Kahle, Philipp J., additional, Melki, Ronald, additional, Luk, Kelvin, additional, Landeck, Natalie, additional, Matharu, Naunehal S., additional, Herling, Therese W., additional, Häsler, Lisa M., additional, Reimann, Regina, additional, Heinzer, Daniel, additional, Avar, Merve, additional, Gonzalez-Guerra, Andrès, additional, Bengoa-Vergniory, Nora, additional, Kaganovich, Alice, additional, Langston, Rebekah G., additional, Bacioglu, Mehtap, additional, de Rossi, Pierre, additional, Tantardini, Elena, additional, Barth, Melanie, additional, Schneider, Matthias M., additional, Eninger, Timo, additional, Hruska-Plochan, Marian, additional, De Cecco, Elena, additional, and Emmenegger, Marc, additional

Published
2021
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22. LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies

Author

Emmenegger, Marc, primary, De Cecco, Elena, additional, Hruska-Plochan, Marian, additional, Eninger, Timo, additional, Schneider, Matthias M., additional, Barth, Melanie, additional, Tantardini, Elena, additional, de Rossi, Pierre, additional, Bacioglu, Mehtap, additional, Langston, Rebekah G., additional, Kaganovich, Alice, additional, Bengoa-Vergniory, Nora, additional, Gonzalez-Guerra, Andrès, additional, Avar, Merve, additional, Heinzer, Daniel, additional, Reimann, Regina, additional, Häsler, Lisa M., additional, Herling, Therese W., additional, Matharu, Naunehal S., additional, Landeck, Natalie, additional, Luk, Kelvin, additional, Melki, Ronald, additional, Kahle, Philipp J., additional, Hornemann, Simone, additional, Knowles, Tuomas P. J., additional, Cookson, Mark R., additional, Polymenidou, Magdalini, additional, Jucker, Mathias, additional, and Aguzzi, Adriano, additional

Published
2021
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23. Early Aβ reduction prevents progression of cerebral amyloid angiopathy

Author

Schelle, Juliane, primary, Wegenast‐Braun, Bettina M., additional, Fritschi, Sarah K., additional, Kaeser, Stephan A., additional, Jährling, Nina, additional, Eicke, Daniel, additional, Skodras, Angelos, additional, Beschorner, Natalie, additional, Obermueller, Ulrike, additional, Häsler, Lisa M., additional, Wolfer, David P., additional, Mueggler, Thomas, additional, Shimshek, Derya R., additional, Neumann, Ulf, additional, Dodt, Hans‐Ulrich, additional, Staufenbiel, Matthias, additional, and Jucker, Mathias, additional

Published
2019
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24. Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition

Author

Schelle, Juliane, primary, Häsler, Lisa M., additional, Göpfert, Jens C., additional, Joos, Thomas O., additional, Vanderstichele, Hugo, additional, Stoops, Erik, additional, Mandelkow, Eva‐Maria, additional, Neumann, Ulf, additional, Shimshek, Derya R., additional, Staufenbiel, Matthias, additional, Jucker, Mathias, additional, and Kaeser, Stephan A., additional

Published
2016
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26. Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Author

Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa M, Schweighauser, Manuel, Wuttke, Thomas V, Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp J, Shimshek, Derya R, Koch, Henner, Jucker, Mathias, and Tanriöver, Gaye

Subjects
Alpha-synuclein, Inclusion Bodies, Neurons, Mice, Organ Culture Techniques, Synucleinopathies, Neurofilament Proteins, Animals, Humans, Microglia, Slice culture, Neurofilament light chain, 3. Good health
Abstract

BACKGROUND: Proteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression. METHODS: Alpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed. RESULTS: To study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2-3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture's genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-year-old donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions. CONCLUSION: The successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments.

27. Additional file 3 of Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Author

Barth, Melanie, Bacioglu, Mehtap, Schwarz, Niklas, Novotny, Renata, Brandes, Janine, Welzer, Marc, Mazzitelli, Sonia, Häsler, Lisa M., Schweighauser, Manuel, Wuttke, Thomas V., Kronenberg-Versteeg, Deborah, Fog, Karina, Ambjørn, Malene, Alik, Ania, Melki, Ronald, Kahle, Philipp J., Shimshek, Derya R., Koch, Henner, Jucker, Mathias, and Tanriöver, Gaye

Subjects
3. Good health
Abstract

Additional file 3: Supplementary Fig. 3 αS aggregates in αS pff and tg brain homogenate. (A, B) HTRF-FRET immunoassay analysis of aggregated αS in αS pff (light grey), tg brain homogenate (dark grey), and wt homogenate (white) at different sample dilutions. Data is reported as ratio of 665 nm / 620 nm × 10,000. Note that αS pff showed Hook effect at dilutions

28. LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies.

Author

Emmenegger M, De Cecco E, Hruska-Plochan M, Eninger T, Schneider MM, Barth M, Tantardini E, de Rossi P, Bacioglu M, Langston RG, Kaganovich A, Bengoa-Vergniory N, Gonzalez-Guerra A, Avar M, Heinzer D, Reimann R, Häsler LM, Herling TW, Matharu NS, Landeck N, Luk K, Melki R, Kahle PJ, Hornemann S, Knowles TPJ, Cookson MR, Polymenidou M, Jucker M, and Aguzzi A

Subjects
Animals, Humans, Mice, Mice, Transgenic, Neurons, alpha-Synuclein genetics, Parkinson Disease, Synucleinopathies
Abstract

While the initial pathology of Parkinson's disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Published
2021
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