| First Author | Barth M | Year | 2021 |
| Journal | Mol Neurodegener | Volume | 16 |
| Issue | 1 | Pages | 54 |
| PubMed ID | 34380535 | Mgi Jnum | J:314354 |
| Mgi Id | MGI:6766214 | Doi | 10.1186/s13024-021-00471-2 |
| Citation | Barth M, et al. (2021) Microglial inclusions and neurofilament light chain release follow neuronal alpha-synuclein lesions in long-term brain slice cultures. Mol Neurodegener 16(1):54 |
| abstractText | 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 (alphaS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An alphaS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the alphaS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed. RESULTS: To study initial stages of alpha-synucleinopathies, we induced alphaS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of alphaS 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 alphaS inclusions was dependent on the type of alphaS seed and on the culture's genetic background (wildtype vs A53T-alphaS genotype). Formation of alphaS 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 alphaS seeds resulted in spreading of alphaS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an alphaS 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 alphaS lesions was achieved at 1week post-seeding in combination with viral A53T-alphaS expressions. CONCLUSION: The successful translation of these brain cultures from mouse to human with the first reported induction of human alphaS 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. |
