Distinct Chronology of Neuronal Cell Cycle Re-Entry and Tau Pathology in the 3xTg-AD Mouse Model and Alzheimer's Disease Patients

Abstract .Cellcyclere-entryinAlzheimer’sdisease(AD)hasemergedasanimportantpathologicalmechanismintheprogressionof the disease. This appearance of cell cycle related proteins has been linked to tau pathology in AD, but the causal and temporalrelationship between the two is not completely clear. In this study, we found that hyperphosphorylated retinoblastoma protein(ppRb), a key regulator for G1/S transition, is correlated with a late marker for hyperphosphorylation of tau but not with otherearly markers for tau alteration in the 3xTg-AD mouse model. However, in AD brains, ppRb can colocalize with both early andlatermarkersfortaualterations,andcanoftenbefoundsinglyinmanydegeneratingneurons,indicatingthedistinctdevelopmentof pathology between the 3xTg-AD mouse model and human AD patients. The conclusions of this study are two-fold. First,our findings clearly demonstrate the pathological link between the aberrant cell cycle re-entry and tau pathology. Second, thechronological pattern of cell cycle re-entry with tau pathology in the 3xTg-AD mouse is different compared to AD patientssuggesting the distinct pathogenic mechanism between the animal AD model and human AD patients.Keywords: Alzheimer’s disease, animal model, cell cycle, retinoblastoma protein (Rb), tau, transgenic mouse