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  • Roles of Id1/HIF-1 and CDK5/HIF-1 in cell cycle reentry induced by amyloid-beta peptide in post-mitotic cortical neuron.

Roles of Id1/HIF-1 and CDK5/HIF-1 in cell cycle reentry induced by amyloid-beta peptide in post-mitotic cortical neuron.

Biochimica et biophysica acta. Molecular cell research (2019-12-31)
A-Ching Chao, Chien-Hui Chen, Ming-Hsuan Wu, Bo-Yu Hou, Ding-I Yang
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Roscovitine, A potent, reversible, and selective inhibitor of Cdks that exhibits about 10-fold greater efficacy towards p34-cdk1 and p33-cdk2 and 20-fold greater efficacy towards p33-cdk5 relative to Olomoucine.
Sigma-Aldrich
Cobalt(II) chloride hexahydrate, BioReagent, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
2-Methoxyestradiol, powder
Sigma-Aldrich
Amyloid β-Protein Fragment 25-35, ≥97% (HPLC)