TI - The mechanism underlying AAV-Tau neurodegeneration . AB - Importantly , the mechanism whereby AAV-Tau inflicts neurodegeneration does not depend on the formation of large , fibrillar tau-aggregates . Conversely , surviving pyramidal neurons flanking the degenerated neurons in CA1/2 , contained hyper-PHOSphorylated tau aggregates , but nevertheless appeared morphologically intact . This remarkable outcome corroborates our previous observation in bigenic mice with massive forebrain tauopathy , i.e.fibrillar tau is not neurotoxic per se [24] . Moreover , the combined data support the hypothesis that fibrillar tau-aggregates function as a sink , to protect neurons against smaller tau-aggregates or -oligomers that are the real neurotoxic species [24] , [36] . The biochemical and physical properties of the postulated neurotoxic tau-oligomers can eventually be defined in the AAV-model , and compared to those in transgenic models . Nevertheless , that might prove a non-conclusive exercise , as discussed below . Particularly mice with inducible tau .lt @@@@@ gt P301L expression showed neurodegeneration and tangles but at much higher expression levels of the mutant tau .lt @@@@@ gt P301L [36] . To our knowledge , models based on wild-type Tau.lt @@@@@ gt 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 PHOSphorylated epitopes in the AAV models , as in our transgenic mice [23] , [24] . No specific single or complex PHOSphorylated 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 combinations of PHOSphorylations of protein tau underlie its neurotoxicity [1] -[11] , [15] -[17] , [31] . 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 PHOSphorylated epitopes 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 tau-species 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 tau-mediated 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 [37] . 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 .