In an experimental model, absence of protein tau alleviated the cognitive defects inflicted by amyloid,Z-VAD-FMK while expressing human wild-type tau causes no or minimal tauopathy. Conversely, mice expressing mutant tau associated with familial fronto-temporal dementia recapitulate robust tauopathy. Bigenic and multiple transgenic mice expressing various combinations of mutant APP and mutant tau recapitulate the combined amyloid and tau-pathology of AD, but lack neurodegeneration and brain-atrophy typical for AD. Here we expressed Tau or APP, both wild-type and mutants, by adeno-associated viral vectors injected directly into the hippocampus of wild-type mice. The observed dramatic pyramidal neuro-degeneration inflicted by wild-type Tau4R and by mutant Tau-P301L within weeks,Regorafenib contrasted with mutant APP that provoked amyloid pathology after 6 months but with only minor neurodegeneration. Importantly, tau-mediated neurodegeneration was not caused by fibrillar tau-aggregates. Most prominent were cell-cycle markers, indicating that degenerating neurons were attempting to re-entry the cell-cycle. The in vivo AAV-based models firmly support the unifying hypothesis that protein tau mediates neurodegeneration by forcing post-mitotic neurons to re-enter the cell-cycle in primary and secondary tauopathies. Initial experiments were performed with triple mutant APP.-SLA, described in the next paragraph, and mutant Tau.P301L, both packaged in AAV-vectors with hybrid serotype-1/2. Intracerebral injection of these vectors into the hippocampal complex of wild-type mice, expresses the embedded cDNA under control of the human synapsin-1 promoter, specifically in pyramidal neurons of hippocampus and cortex. The generated triple mutant APP.SLA construct contained the Swedish, London and Austrian mutations that are associated with early-onset familial AD. Transient expression in neuro-blastoma cells demonstrated APP.SLA to produce highest levels of Ab42. Tau.P301L is associated with FTDP-17 and produced experimentally robust tauopathy in single and bigenic mice by us and others. Initially, brains were analyzed 12 weeks after intracerebral injection of AAV-vectors in wild-type mice.