During neurodegenerative disorders such as Alzheimer’s disease, the protein tau forms dense aggregates inside cells of the brain. The question of how this pathology spreads from once cell to another during the progression of disease is a matter of debate. Aggregates could form spontaneously within each cell, or might spread in a prion-like or virus-like manner where aggregated tau ‘seeds’ normal tau, producing further aggregates. Understanding which of these processes dominates is important as it will inform how best to interfere with the process for medical benefit.
A recent paper from the LMB team in Acta Neuropathologica Communications has shed light on this issue. They developed a new model of tau pathology by culturing thin slices of mouse brain in lab conditions over periods of weeks. The model allowed precise control over the concentration of tau seeds that the system is exposed to, in contrast to living animals where this is hard to achieve. This meant that the authors could see what happens when slices were exposed to very low levels of tau, similar to those found in the brain. Seeded aggregation of tau occurred readily at high concentrations of tau seed, as expected. Surprisingly however, seeded aggregation entirely disappeared when physiological concentrations of tau were used. The results suggest that healthy brain tissue possesses mechanisms that resist tau seeding at low concentration.
The study suggests that tau aggregates may occur by forming independently in each cell during disease, or that the mechanisms of resistance are lowered in the diseased brain tissue to allow prion-like spread. Understanding how cells resist seeding may therefore uncover new targets to prevent tau pathology spreading during neurodegeneration.
Timeline of organotypic hippocampal slice culture preparation and treatment; schematic of the production of Organotypic hippocampal slice cultures (OHSCs) and resulting imaging.
This project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking (www.imi.europa.eu) under grant agreement No 116060. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038.
The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.