Modeling Tau-Mediated Pathology in Monkey Brain Slices

Tau pathology is a hallmark feature of Alzheimer’s disease (AD) and is tightly associated with clinical manifestations. No disease-modifying therapy is currently available for AD, partly due to prominent interspecies differences in tau expression patterns between rodents and primates. To facilitate the investigation of primate-specific tau pathology, we developed an in vitro platform using monkey (Macaca fascicularis) brain slice cultures (BSC) that preserve native three-dimensional tissue architecture and maintain functional networks closely mirroring in vivo conditions. We systematically evaluated various adeno-associated virus (AAV) serotypes and promoter combinations to achieve efficient transgenic tau expression. Our data confirm that the monkey BSC system is highly amenable to AAV-mediated gene delivery, exhibiting robust transduction of glial cells with minimal cytotoxicity and allowing for the examination of glial pathology induced by disease-associated proteins. Notably, this platform is applicable to both juvenile and aged specimens, enabling comparative analyses of age-dependent susceptibility to pathological insults. Following overexpression of mutant human tau, we observed time-dependent tau pathology development within 2–4 weeks post-infection, including hyperphosphorylation and aggregation. This in vitro primate model offers a unique opportunity to dissect primate-specific pathological events. Furthermore, the scalability and reproducibility of this system render it ideally suited for drug screening, providing a more translationally relevant preclinical bridge between rodent models and human clinical trials.