TI - Cell cycle re-entry . AB - In AD and unrelated tauopathies , cell -cycle events are suggested to correlate with , if not cause neuro-degeneration . Specifically , cell -cycle activation caused neurodegeneration in a Drosophila tauopathy model [38] . Here we discuss only our most marked experimental data that support the conclusion that cell -cycle re-entry is prominent in the AAV-Tau model . Supporting data and many remaining problems of this hypothesis are reviewed elsewhere [31] -[35] . Cyclins B1 and D2 were most prominent in degenerating CA1 neurons of AAV-Tau mice . Cyclins D1 , D2 , D3 with cdk4 and cdk6 , regulate G1/S transition by releasing E2F transcription factors via increased PHOSphorylation of retinoblastoma protein . The latter is here also demonstrated in degenerating pyramidal neurons expressing protein Tau . Upregulation of cyclinB1 also points to the G2/M checkpoint , which depends on cdk2/cyclinB1 activity . Both cyclinD2 and cyclinB1 have been shown to mark cell -cycle events in AD brain [39] . The proliferating cell nuclear antigen ( PCNA ) marked a subset of CA1 pyramidal neurons , but these were , surprisingly , not marked by proliferation marker Ki67 . This is particularly interesting in view of the role of PCNA in DNA repair [40] . The fact that cyclinD2 deficient mice that have problems with adult neurogenesis [35] did suffer no less neurodegeneration induced by AAV.Tau than wild-type mice , corroborates that cell cycle control , and induction of the post-mitotic state , is not left to one component or complex . Rather , or alternatively , the contribution of the cell -cycle to neurodegeneration would be by multi-point or by fragmented reentry attempts , whereby cyclinD2 is not the decisive factor , or is made redundant by cyclins D1 and D3 [35] . Among candidate factors that could force post-mitotic neurons to re-enter the cell -cycle are mitogenic factors from the MAPK family , e.g . p44/42 MAPK ( Erk1/2 ) , p38 MAPK and SAPK/JNK . While JNK/SAPK was not detected and p44/42 MAPK was observed in glial cells , only p38 MAPK was markedly increased in degenerating neurons in tau mice . Similarly , whereas Akt/PKB is a central regulator of metabolism , apoptosis , transcription and cell -cycle , this kinase appeared not activated in the AAV-Tau model . From the many markers analyzed ( Tables S1 , S2 ) we conclude that the strongest indications support the hypothesis that neurons degenerate because of their attempts to re-enter the cell -cycle . Nevertheless , other markers are observed and proposed to contribute , not in the least microgliosis , as discussed below . Activated microglia are spatially and temporally closely associated with degenerating neurons in the tau models , strongly resembling the pathological characteristics of mice with hippocampal and cortical sclerosis [28] .