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

Springer Science and Business Media LLC - Tập 16 - Trang 1-17 - 2021
Melanie Barth1,2,3, Mehtap Bacioglu1,2,3, Niklas Schwarz4, Renata Novotny1,2, Janine Brandes2,5, Marc Welzer1,2,3, Sonia Mazzitelli1,2, Lisa M. Häsler1,2, Manuel Schweighauser1,2, Thomas V. Wuttke5,6, Deborah Kronenberg-Versteeg1,2, Karina Fog7, Malene Ambjørn7, Ania Alik8, Ronald Melki8, Philipp J. Kahle1,9, Derya R. Shimshek10, Henner Koch5,11, Mathias Jucker1,2, Gaye Tanriöver1,2
1DZNE, German Center for Neurodegenerative Diseases, Tuebingen, Germany
2Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
3Graduate Training Center of Neuroscience, University of Tuebingen, Tuebingen, Germany
4Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
5Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
6Department of Neurosurgery, University of Tuebingen, Tuebingen, Germany
7Division of Neuroscience, H. Lundbeck A/S, Valby, Denmark
8MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, Institut François Jacob, Fontenay-aux-Roses, France
9Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany
10Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland
11Department of Epileptology, Neurology, RWTH Aachen University, Aachen, Germany

Tóm tắt

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. 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. 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. 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.

Tài liệu tham khảo

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