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

One neurotoxic mechanism of amyloid-beta peptide (A beta), 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 A beta 25-35-treated primary rat cortical neurons as the experimental system, in the present study we tested whether A beta-induced inhibitor of differentiation-1 (Id1)/hypoxia-inducible factor-1alpha (HIF-1 alpha) and cyclin-dependent kinase-5 (CDK5) contribute to cell cycle reentry in fully differentiated post-mitotic neurons. We found that Id1-induced HIF-1 alpha mediated A beta 25-35-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. A beta 25-35 also enhanced p35 cleavage to p25 without affecting CDK5 expression. The CDK5 inhibitor roscovitine and the siRNA targeting CDK5 both suppressed A beta 25-35-dependent HIF-1 alpha expression and cell cycle reentry. Intriguingly, A beta 25-35-induced Id1 repressed p25 production while CDK5/p25 reciprocally inhibited Idl expression, despite the observation that both Id1 and CDK5/p25 acted upstream of HIF-l alpha. These results demonstrated that both Id1/HIF-1 and CDK5/HIF-1 contribute to All-induced cell cycle reentry in post-mitotic neurons; furthermore, Id1 and CDK5/p25 reciprocally suppress expression of each other.