MAPT regulates autophagic-lysosomal function and phagocytosis in human microglia

Tauopathies are brain disorders marked by the accumulation and spread of tau protein aggregates, affecting not only neurons but also microglia, a type of immune cell. Researchers created microglia from human stem cells, some carrying a mutation in the MAPT gene associated with tau pathology. The study found that the mutated microglia had weakened lysosomal function, a cellular process for breaking down waste, compared to healthy microglia.

The mutated microglia showed reduced levels of lysosomal enzymes, the machinery for degrading unwanted cellular components. They also had impaired autophagy, the process of recycling cellular waste, and were less efficient at engulfing and breaking down tau aggregates. Mutant microglia also struggled to take up tau aggregates from their surroundings and accumulated tau in acidic compartments within the cell.

Interestingly, when the team genetically removed the MAPT gene, the microglia regained their lysosomal function and were able to more effectively manage tau aggregates. This suggests that normal tau levels help maintain the microglia's ability to degrade and clear tau pathology. The researchers also tested whether boosting the autophagy-lysosome pathway could help the mutated microglia, and found that it did improve their tau handling abilities.

In summary, the study reveals a complex relationship between tau proteins and microglial lysosomal function. Mutations in the MAPT gene that lead to tau pathology appear to dampen the microglia's capacity to clear tau aggregates through lysosomal and autophagic processes. Conversely, reducing tau levels appears to enhance these cellular functions. The findings suggest that modulating tau levels could potentially boost the microglia's degradative capacity and aid in combating tau-related brain disorders.