Here, tau was overexpressed following injection of AAV2/6 vectors in the lateral ventricles of neonatal mice. The main advantage of this approach is to induce widespread expression of the protein throughout the mouse forebrain, which is most prominently, but not exclusively observed in the long-projection pyramidal neurons located in the cortex and hippocampus. It is therefore possible to directly compare the pathogenic effects of various forms of tau, when overexpressed at similar levels. Remarkably, this model system leads to a prominent pathology, characterized by tau hyperphosphorylation and misfolding, which is already observed after a few weeks. In the normal brain, the tau protein appears to be transiently hyperphosphorylated during the early postnatal period, although the pattern of tau isoforms expressed during this period is different from the adult brain32–35. The overexpressed 4R0N tau isoform might as well be subject to hyperphosphorylation during the early postnatal period, initiating pathological changes that may persist or further progress during adulthood.