Deciphering early tau pathology events using an Alzheimer’s disease-seeded organotypic hippocampal slice culture model

In Alzheimer's disease, the spreading of the tau pathology through the brain is assumed to rely on pathological species of tau acting as seeds. To better understand the underlying mechanisms, we need models allowing us to study tau seeding in a brain-like environment. We developed an ex vivo model based on organotypic hippocampal slice cultures prepared from transgenic mouse pups expressing human pro-aggregative mutant tau. We show for the first time that human brain-derived tau seeds are able to potentiate tau pathology in such cultures. Moreover, tau seeds are generated ex vivo , completing the validation of the model. Then, we shed light on the initial events of tau seeding: tau pathology appears sequentially, first in neurites and then in cell bodies, and misfolding (MC1+) precedes pathological phosphorylation (pS422, pT217). Altogether, this makes the present model a highly valuable bioassay to decipher the molecular and cellular mechanisms leading to tau pathology development.