1. Roles of Id1/HIF-1 and CDK5/HIF-1 in cell cycle reentry induced by amyloid-beta peptide in post-mitotic cortical neuron.
- Author
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Chao, A-Ching, Chen, Chien-Hui, Wu, Ming-Hsuan, Hou, Bo-Yu, and Yang, Ding-I
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CELL cycle , *AMYLOID plaque , *PROLIFERATING cell nuclear antigen , *MITOSIS , *NEUROFIBRILLARY tangles , *COBALT chloride , *NEURONS - Abstract
One neurotoxic mechanism of amyloid-beta peptide (Aβ), the major component of senile plaques in the brains of Alzheimer's disease (AD) patients, is to trigger cell cycle reentry in fully differentiated neurons. However, the detailed underlying mechanisms remain unclear. Using Aβ25-35–treated primary rat cortical neurons as the experimental system, in the present study we tested whether Aβ-induced inhibitor of differentiation-1 (Id1)/hypoxia-inducible factor-1alpha (HIF-1α) and cyclin-dependent kinase-5 (CDK5) contribute to cell cycle reentry in fully differentiated post-mitotic neurons. We found that Id1-induced HIF-1α mediated Aβ25-35–dependent expression of the cell cycle markers cyclin D1 and proliferating cell nuclear antigen (PCNA), both colocalized with microtubule-associated protein-2 (MAP-2) + cells, indicative of cell cycle reentry in the mature neurons. Aβ25-35 also enhanced p35 cleavage to p25 without affecting CDK5 expression. The CDK5 inhibitor roscovitine and the siRNA targeting CDK5 both suppressed Aβ25-35–dependent HIF-1α expression and cell cycle reentry. Intriguingly, Aβ25-35–induced Id1 repressed p25 production while CDK5/p25 reciprocally inhibited Id1 expression, despite the observation that both Id1 and CDK5/p25 acted upstream of HIF-1α. These results demonstrated that both Id1/HIF-1 and CDK5/HIF-1 contribute to Aβ-induced cell cycle reentry in post-mitotic neurons; furthermore, Id1 and CDK5/p25 reciprocally suppress expression of each other. • Id1-dependent HIF-1 induction contributes to Aβ25-35-mediated cell cycle reentry in post-mitotic cortical neurons. • Id1 and cobalt chloride capable of stabilizing HIF-1α are both sufficient to directly trigger neuronal cell cycle reentry. • Aβ25-35-induced p25 production is required for HIF-1α induction and neuronal cell cycle reentry. • Id1 and CDK5/p25 show antagonism in suppressing expression of each other in cortical cultures. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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