Hippocampal neurons in our mice that model hippocampal sclerosis by inducible expression of p25, the truncated activator of cdk5. Other pathological features like tangles, spheroids and axonal dilatations were revealed by various staining methods, but only sporadically and not consistently in all AAV-Tau injected mice. Neither their localization nor distribution nor abundance could explain the observed massive pyramidal cell-death. This remarkable outcome corroborates our previous observation in bigenic mice with massive forebrain tauopathy, i.e. fibrillar tau is not neurotoxic per se. Moreover, the combined data support the hypothesis that fibrillar tau-aggregates function as a sink, to protect neurons against smaller tauaggregates or -oligomers that are the real neurotoxic species. The biochemical and physical properties of the postulated neurotoxic tau-oligomers can eventually be defined in the AAVmodel, and compared to those in Catharanthine sulfate transgenic models. Nevertheless, that might prove a non-conclusive exercise, as discussed below. Particularly mice with inducible tau.P301L expression showed neurodegeneration and tangles but at much higher expression levels of the mutant tau.P301L. To our knowledge, models based on wild-type Tau.4R have not been reported to suffer appreciable neurodegeneration in the hippocampus. We analyzed the phosphorylation status of tau and collected extensive biochemical and immuno-histochemical data-sets on tau phospho-epitopes in the AAV models, as in our transgenic mice. No specific single or complex phospho-epitope on tau is identified as essential for, or directly related to the neurodegeneration. This is not unexpected, and in line with many studies on human brain and in experimental models, supporting the conviction that variable Mepiroxol combinations of phosphorylations of protein tau underlie its neurotoxicity. By logical extension, not a single kinase but combined actions of several kinases are to be hold responsible for phosphorylating tau to make it eventually harmful to neurons. Moreover, the sets of phosphoepitopes and of kinases most likely will vary pending the affected brain region, i.e. the disorder. Because tauopathies vary widely in their clinical, pathological and biochemical characteristics, the molecular identification of a unique, unifying neurotoxic tauspecies becomes more and more unlikely. We first and foremost consider important the only known physiological function of protein tau, i.e. binding to microtubules. If phosphorylated protein tau fails to stabilize microtubules, or affects microtubule dynamics, a dysfunctional cytoskeleton with axonal, dendritic and synaptic defects as results. The observed changes in cytoarchitecture in degenerating neurons, support the hypothesis that they contribute to the overall process. The experimental data obtained with truncated Tau255 most strongly imply that microtubule binding of protein tau is essential in inflicting neurodegeneration and involve the microtubular network as a structural and transport scaffold. The alternative explanation, i.e. that wild-type and mutant full-length Tau but not truncated Tau255 interact with cellular proteins other than microtubuli, remains open for experimental verification. We went on to define the underlying mechanism of taumediated neurodegeneration by analysis of a large and wide panel of molecular targets and pathways, conform the hypothesis that neurons do not die by a single mechanism. Although the outcome did not yield a single mechanism to be responsible for tau-mediated neuronal cell-death, the indications for attempted cell-cycle reentry were most marked.