ABSTRACTThe aggregation of tau proteins into insoluble filaments and the spread of these filaments across brain regions are the major drivers of neurodegeneration in tauopathies, including in Alzheimer’s disease (AD). Apolipoprotein E4 (APOE4), a crucial genetic risk factor for late-onset AD, has been shown to exacerbate tau pathology in mouse models. However, the exact mechanisms through which APOE4 induces tau pathology remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), which we identify as a novel binding partner of APOE4, drives tau pathology. We discovered that GPC-4 preferentially interacts with APOE4 in comparison to APOE2, considered to be a protective allele to AD, and post-mortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. The astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9 mediated activation of GPC-4 in a tauopathy mouse model robustly induced tau pathology. Using in vitro Tau FRET-biosensor cells, human iPSCs-derived astrocytes and an in vivo mouse model, we found that APOE4-induced tau pathology was greatly diminished in the absence of GPC-4. We further show that APOE4-mediated surface trafficking of APOE receptor low-density lipoprotein receptor-related protein 1 (LRP1) through GPC-4 can be a gateway to tau spreading. Together, our data comprehensively demonstrate that APOE4-induced tau pathologies are directly mediated by GPC-4.