The role of human microglia and microglial LRRK2 in tau pathogenesis

The G2019S mutation in leucine‐rich repeat kinase 2 (LRRK2) is the most common genetic determinant of Parkinson’s disease (PD), reported in both familial and sporadic PD cases. Even though tau‐positive pathology features prominently in the G2019S PD patients, the role of LRRK2 in tau pathogenesis remains poorly understood. Human microglia – the chief brain‐resident phagocytes of the innate immune system ‐ become one of the highest LRR2K expressing cells upon IFN‐y stimulation. Moreover, microglia have been recently implicated in increasing pathological tau transmission by secreting exosome‐bound, seeding‐competent tau into the extracellular space. Using human iPS‐macrophages, a simple but physiologically relevant and genetically tractable model of human microglia, we set out to define the role of microglial LRRK2 in uptake, degradation, and secretion of disease‐associated tau protein.