Tau processing and tau-mediated inflammation differ in human APOEε2 and APOEε4 astrocytes

Alzheimer's disease (AD) and progressive supra-nuclear palsy (PSP) are both proteinopathies, characterized by the accumulation of tau aggregates. <i>APOEε4</i> is the greatest genetic risk factor for developing AD, while <i>APOEε2</i> is a significant risk factor for developing PSP. In the brain, astrocytes are the predominant producer of ApoE, but they are also important for inflammation and overall brain homeostasis. Although, tau inclusions appear frequently in astrocytes in both AD and PSP brains, their connection to ApoE remains unclear. Here, we show that hiPSC-derived <i>APOE 2/2</i> astrocytes accumulate, process, and spread pathogenic tau aggregates more efficiently than isogenic <i>APOE 4/4</i> astrocytes. Moreover, the <i>APOE 2/2</i> astrocytes display a more robust inflammatory response, which could be of relevance for the disease course. Taken together, our data highlight a central role of ApoE in astrocyte-mediated tau pathology.