Understanding the mechanisms of neuronal spread, and role of microglia, in neurodegeneration using mouse and human organotypic slice culture seeding models

11/12/2020 to 30/09/2022

Alzheimer’s Disease and Parkinson’s Disease (PD) are disorders of the central nervous system. Current hypotheses suggest that protein misfolding and the associated prion-like pathogenic spread of misfolded protein aggregates are common underlying features of these “proteinopathies” that lead to progressive neurodegeneration and neuroinflammation in affected patients. The Jucker Lab at the University of Tuebingen and DZNE Tuebingen has developed an organotypic slice culture model for Alpha-Synuclein (ASyn)-induced seeding and spreading to study pathogenic mechanisms related to PD. The model demonstrates progressive spread of ASyn pathology which correlates with increased levels of neurodegeneration markers (neurofilament light chain) over the course of several weeks in culture. The majority of studies characterizing this model have been conducted using mouse tissues, however the lab has extended the model to human-derived brain tissues. This would enable the translation of key findings related to pathway validation and target engagement, from mouse to human tissues, overcoming a hurdle currently faced in the field. The main aims of this collaboration are to identify key mechanisms and pathways engaged, validate therapeutic hypotheses related to the pathogenic spread of misfolded proteins, and determine if this model is suitable for testing the efficacy of pre-clinical lead candidate molecules.