Cerebral proteopathies such as Alzheimer´s disease and Parkinson´s disease are human age-related disorders that do not naturally arise in animals. Proteopathic lesions develop many years, if not decades before the first symptoms occur, and lesions at death are likely to be different from the ones driving the disease. Moreover, the cell-to-cell spreading of proteopathic lesions is largely a cell-non-autonomous process and largely dependent on the host environment. Thus, cerebral proteopathies are best studied in a living environment that closely mimics the adult or aged brain. While mice have been instrumental in the past to study such the induction and propagation of pathogenic seeds, mouse models are time-consuming, costly, and experimental manipulations to mechanistically understand the disease often challenging.

To this end the DZNE team has developed long-term slice cultures from postnatal mouse brain and achieved the seeded induction and propagation of murine and human α-syn inclusions in a complex cellular brain environment. We find that microglia inclusions follow the neuronal α-synuclein lesions upon seeded induction. We also identified a human anti-α-syn antibody that blocks the induction of these lesions and also the spreading along neural pathways. To foster translation, progression of α-synucleinopathy could be monitored by the neurofilament light chain protein release into the culture medium, a biomarker used in preclinical animal studies as well as in clinical settings.

Their paper published in the journal Molecular Neurodegeneration presents this recent milestone finding that brain slices derived from surgical resections are stable in vitro for up to three weeks if cultured in human cerebral spinal fluid. Thus, we applied the parameters from the murine cultures to the resection-derived adult human brain tissue cultures and succeeded in inducing α-syn inclusion in a true adult human brain environment.

Distribution of aggregates in tg hippocampal sluce cultures treated analysed at 5 weeks post-treatment.

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