Affiliations: [a] Center for Neuroscience and Cell Biology, Faculty of Medicine, Biochemistry Institute, University of Coimbra, Coimbra, Portugal | [b] Department of Neurobiology and Behavior, 1109 Gillespie Neuroscience Facility, University of California, Irvine, CA, USA
Correspondence:
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Corresponding author: Joao Pedro Lopes, Center for Neuroscience and Cell Biology, Faculty of Medicine, Biochemistry Institute, University of Coimbra, 3004 Coimbra, Portugal. Tel.: +351 239 820190; Fax: +351 239 822776; E-mail: jpplopes@gmail.com.
Abstract: 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-β (Aβ) plaques and tau-laden neurofibrillary tangles, remains unclear. We sought to determine whether cell cycle reactivation initiates in direct response to Aβ 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-DTA 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-DTA 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 Aβ or tau pathology, but rather appears to be triggered by acute neuronal loss.
