TY - JOUR TI - Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures AU - Barth, Melanie AU - Bacioglu, Mehtap AU - Schwarz, Niklas AU - Novotny, Renata AU - Brandes, Janine AU - Welzer, Marc AU - Mazzitelli, Sonia AU - Häsler, Lisa M. AU - Schweighauser, Manuel AU - Wuttke, Thomas V. AU - Kronenberg-Versteeg, Deborah AU - Fog, Karina AU - Ambjørn, Malene AU - Alik, Ania AU - Melki, Ronald AU - Kahle, Philipp J. AU - Shimshek, Derya R. AU - Koch, Henner AU - Jucker, Mathias AU - Tanriöver, Gaye T2 - Molecular Neurodegeneration AB - 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. DA - 2021/12// PY - 2021 DO - 10.1186/s13024-021-00471-2 DP - DOI.org (Crossref) VL - 16 IS - 1 SP - 54 J2 - Mol Neurodegeneration LA - en SN - 1750-1326 UR - https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00471-2 Y2 - 2021/09/07/09:34:30 KW - highlight KW - peer-reviewed ER -