Alzheimer’s disease (AD) is characterised by the aberrant aggregation of two proteins within the brain- amyloid-β which deposits in extracellular plaques and the tau protein which forms neurofibrillary tangles. However, it is tau spreading that best correlates with clinical symptoms in AD, whilst the mechanisms that potentially drive tau spreading remain still unknown. More recently a study has demonstrated that binding of tau fibrils to the extracellular region of the Amyloid Precursor Protein (APP) led to the uptake of tau into cells, suggesting that APP may function as a tau fibril receptor during the trans-neuronal spreading of tau, thereby contributing to disease progression. To address whether APP modulates tau pathology spreading in vivo, we combined relevant Alzheimer’s disease mouse models with recently developed AAV- based reporter constructs, brain slice stimulations and microfluid chambers. This approach allowed us to stepwise uncover underlying molecular pathways of tau release/uptake/and propagation in vivo, and further decipher a novel role of APP in tau pathology spreading. More specifically, our data shows that APP facilitates the induction of tau pathology and promotes neuronal release and spreading of tau in vivo. Further our finding demonstrate that this process is amplified by pathogenic APP mutations as well as increased levels of APP. Accordingly, depletion of APP significantly reduced this effect, resulting in less seeding and spreading of tau. In summary, our data points to APP as being an integral part of tau pathology spreading and further delineates a novel role for pathogenic APP mutations in AD.