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

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

Long-term adult human brain slice cultures as a model system to study human CNS circuitry and disease

Most of our knowledge on human CNS circuitry and related disorders originates from model organisms. How well such data translate to the human CNS remains largely to be determined. Human brain slice cultures derived from neurosurgical resections may offer novel avenues to approach this translational gap. We now demonstrate robust preservation of the complex neuronal cytoarchitecture and electrophysiological properties of human pyramidal neurons in long-term brain slice cultures. Further experiments delineate the optimal conditions for efficient viral transduction of cultures, enabling "high throughput" fluorescence mediated 3D reconstruction of genetically targeted neurons at comparable quality to state-of-the-art biocytin fillings, and demonstrate feasibility of long term live cell imaging of human cells in vitro. This model system has implications toward a broad spectrum of translational studies, regarding the validation of data obtained in non-human model systems, for therapeutic screening and genetic dissection of human CNS circuitry

Des hommes et du masculin

Où en est-on des études, réflexions sur les hommes, le masculin, des rapports homme/femme vus du côté et/ou à partir des hommes ? Quels ont été les apports des différents groupes masculinistes, gays, antisexistes qui ont, après l'interpellation féministe, interrogé de manière plus ou moins directe l'identité masculine, l'inégalité des sexes, les relations hommes/femmes ? Qu'en est-il du genre ? Du masculin dans les rapports sociaux de sexe ? Telles furent quelques-unes des questions qui ont été posées aux chercheurs invités à écrire dans un numéro du BIEF (Bulletin d'information des études féminines) consacré aux hommes. Le BIEF est une revue féministe, éditée par le Centre d'études féminines de l'Université de Provence depuis 1975. Convaincu-e-s de la nécessité d'un débat mixte sur les rapports hommes/femmes, c'est-à-dire sur les rapports sociaux de sexe, les responsables de la revue et ceux du groupe Anthropologie des sexes et de la vie domestique du CREA (Centre de recherches et d'études anthropologiques) de l'Université Lumière-Lyon 2 se sont associé-e-s pour publier cet ouvrage. Les articles traduisent la diversité des recherches menées aujourd'hui par les hommes sur les hommes. Sociologues, philosophes, anthropologues et psychologues de France, du Québec et d'Allemagne décrivent des segments particuliers où se structure l'identité masculine : église, armée, pornographie, homosexualité, violence, paternité assistée par médecin ; d'autres s'interrogent sur le genre masculin et les catégories pour penser ce genre