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 net-work 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,WY 14643 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. The rapid and dramatic neurodegeneration inflicted by protein tau contrasts with the minimal neurotoxic effects sorted by the mutant APP.SLA under the same experimental conditions. Only marginal neuro-degeneration resulted despite important accumu-lation of amyloid peptides that led even at 6 months p.i. to amyloid plaques in hippocampus and cortex. This marked dissociation in outcome by the same experimental approach, corroborates the growing awareness that neurodegeneration in AD is not mediated primarily or directly by amyloid. The essential contribution of protein tau to pyramidal cell-death is thereby joined seamlessly to the primary tauopathies. Consequently,WZ4002 tau pathology is essential and decisive, together with amyloid, in the overall pathogenesis of AD, notwithstanding its pathological classification as a ‘secondary tauopathy’. We adhere the hypothesis that in AD the accumulation of amyloid is the trigger, but that protein tau executes specified neurons. The transgenic models for amyloid and tau pathology have not, however, substantiated this hypothesis to the fullest, although they have been invaluable for understanding molecular mechanisms of amyloid peptide generation, amyloid pathology, repercussions on cognition and behavior.