TI - AAV versus transgenic models . AB - A final important point concerns the question why AAV-based models are more powerful in producing neuro-degeneration than transgenic models expressing the same wild-type Tau4R isoform [41] or Tau.lt @@@@@ gt P301L mutant [23] at similar near-physiological levels . These transgenic models suffer axonopathy and tauopathy , respectively , but without appreciable neurodegeneration . Although data to answer this problem do not abound , we consider as major difference the observed microgliosis that is much more intense in the AAV-Tau model than in the AAV-APP mice . Microgliosis is spatially and temporally most closely associated with degenerating neurons in the tau models . This is strongly reminiscent of our observations in inducible p25 mice that suffer a profound hippocampal and cortical sclerosis with pathological characteristics very similar to the AAV-Tau mice [28] . A recent study described wild-type tau to mediate some neurodegeneration with combined microgliosis by AAV gene -transfer [42] . Therein , degeneration of dopaminergic neurons in the substantia nigra of aged rats was also directly associated with microgliosis , lending support to our assumption that microgliosis contributes essentially to neurodegeneration . Whereas also the viral vectors used as delivery tool , can be of some importance , they are evidently not decisive because neurodegeneration is specific for tau , wild-type and mutant , and was lacking in AAV-APP and AAV-EGFP mice , observed here and as observed in other models [19] , [42] . Aspects that are important to explain the apparently contradictory outcome in different models , relate to differences in time-scale and kinetics whereby neurons either degenerate or whereby tau aggregates and 'sinks' into tangles . It is evident that various post-translational modifications , e.g.PHOSphorylation , ubiquitinylation , glycation , O-glucosylation , ...can and will contribute to either mechanism . The overall process is complex and implies enzymes , i.e.proteinases , kinases , phosphatases , ...but also cellular factors like chaperones and heat-shock proteins . Their structural features and dynamic actions will tilt the balance to either slow death by progressive accumulation of aggregated , undigested or undigestible amyloid and/or protein tau , or to faster death by cell -cycle re-entry , accelerated by microglia derived pro-inflammatory neurotoxic factors [43] . Moreover , the tau-species that are responsible for aggregation and neurotoxicity are proposed to differ at the molecular level . We refer here also to a most recent report on the transmission and spreading of tauopathy in transgenic mouse brain , following intra-cerebral injection of tau-aggregates [44] . Those findings are relevant for the possible cell -to cell spreading of tauopathy in brain and imply an extracellular route , which is to be defined for the cytoplasmic protein tau . Nevertheless , the time-scale of spreading was very slow and resulted in typical tauopathy with aggregates and tangles , while neuro-degeneration was minimal or absent [44] . Thereby , that model conforms to the tauopathy as observed in the parental tau .lt @@@@@ gt P301S transgenic mice that have no neurodegeneration in limbic regions . In conclusion , we present in vivo experimental evidence for a major problem in tauopathies : effective modeling of pyramidal neurodegeneration that is mediated by protein tau .lt @@@@@ gt 4R , which is responsible for the majority of human tauopathies , including all Alzheimer patients . We further delineate two major mechanisms that contribute to the rapid neurodegeneration mediated by AAV-Tau : attempted cell -cycle re-entry by the post-mitotic neurons , and microgliosis . We are confident that these innovative models will contribute considerably to unravel the molecular factors and mechanistic details . Importantly , the ease whereby the AAV-vectors and the models can be implemented widely in research-projects on neurodegeneration is a further strong point of this report . The wider distribution of the model , and its application for analysis of mechanisms that will untangle tau-mediated neurodegeneration , is hoped to help meet the needs of patients suffering from primary tauopathies or Alzheimer's disease .