TY  - JOUR
AU  - Barth, Melanie
AU  - Bacioglu, Mehtap
AU  - Schwarz, Niklas
AU  - Novotny, Renata
AU  - Brandes, Janine
AU  - Welzer, Marc
AU  - Mazzitelli, Sonia
AU  - Häsler, Lisa
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
AU  - Shimshek, Derya R
AU  - Koch, Henner
AU  - Jucker, Mathias
AU  - Tanriöver, Gaye
TI  - Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures.
JO  - Molecular neurodegeneration
VL  - 16
IS  - 1
SN  - 1750-1326
CY  - London
PB  - Biomed Central
M1  - DZNE-2021-01367
SP  - 54
PY  - 2021
N1  - CC BY
AB  - 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.
KW  - Animals
KW  - Humans
KW  - Inclusion Bodies: pathology
KW  - Mice
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Neurofilament Proteins: metabolism
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Organ Culture Techniques: methods
KW  - Synucleinopathies
KW  - alpha-Synuclein: toxicity
KW  - Alpha-synuclein (Other)
KW  - Microglia (Other)
KW  - Neurofilament light chain (Other)
KW  - Slice culture (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34380535
C2  - pmc:PMC8356412
DO  - DOI:10.1186/s13024-021-00471-2
UR  - https://pub.dzne.de/record/162710
ER  -