Activation of cell cycle proteins in transgenic mice in response to neuronal loss but not amyloid-beta and tau pathology.
Cell cycle proteins are elevated in the brain of patients and in transgenic models of Alzheimer's disease (AD), suggesting that aberrant cell cycle re-entry plays a key role in this disorder. However, the precise relationship between cell cycle reactivation and the hallmarks of AD, amyloid-beta (Abeta) plaques and tau-laden neurofibrillary tangles, remains unclear. We sought to determine whether cell cycle reactivation initiates in direct response to Abeta and tau accumulation or whether it occurs as a downstream consequence of neuronal death pathways. Therefore, we used a triple transgenic mouse model of AD (3xTg-AD) that develops plaques and tangles, but does not exhibit extensive neuronal loss, whereas to model hippocampal neuronal death a tetracycline-regulatable transgenic model of neuronal ablation (CaM/Tet-DT(A) mice) was used. Cell-cycle protein activation was determined in these two models of neurodegeneration, using biochemical and histological approaches. Our findings indicate that Cdk4, PCNA and phospho-Rb are significantly elevated in CaM/Tet-DT(A) mice following neuronal death. In contrast, no significant activation of cell-cycle proteins occurs in 3xTg-AD mice versus non-transgenic controls. Taken together, our data indicate that neuronal cell cycle reactivation is not a prominent feature induced by Abeta or tau pathology, but rather appears to be triggered by acute neuronal loss.
Lopes
Joao P
JP
Center for Neuroscience and Cell Biology, Faculty of Medicine, Biochemistry Institute, University of Coimbra, Coimbra, Portugal. jpplopes@gmail.com
Blurton-Jones
Mathew
M
Yamasaki
Tritia R
TR
Agostinho
Paula
P
LaFerla
Frank M
FM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D003714:Denervation; D004195:Disease Models, Animal; D006657:Histones / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D013752:Tetracycline; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018797:Cell Cycle Proteins; D006657:Histones; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; D016875:tau Proteins; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D013752:Tetracycline