Protein Kinase C-Delta Mediates Cell Cycle Reentry and Apoptosis Induced by Amyloid-Beta Peptide in Post-Mitotic Cortical Neurons

Amyloid-beta peptide (A beta) is a neurotoxic constituent of senile plaques in the brains of Alzheimer's disease (AD) patients. The detailed mechanisms by which protein kinase C-delta (PKC delta) contributes to A beta toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, we found that inhibition of A beta 25-35-induced PKC delta increased cell viability with restoration of neuronal morphology. Using cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) as the respective markers for the G1-, S-, and G2/M-phases, PKC delta inhibition mitigated cell cycle reentry (CCR) and subsequent caspase-3 cleavage induced by both A beta 25-35 and A beta 1-42 in the post-mitotic cortical neurons. Upstream of PKC delta, signal transducers and activators of transcription (STAT)-3 mediated PKC delta induction, CCR, and caspase-3 cleavage upon A beta exposure. Downstream of PKC delta, aberrant neuronal CCR was triggered by overactivating cyclin-dependent kinase-5 (CDK5) via calpain2-dependent p35 cleavage into p25. Finally, PKC delta and CDK5 also contributed to A beta 25-35 induction of p53-upregulated modulator of apoptosis (PUMA) in cortical neurons. Together, we demonstrated that, in the post-mitotic neurons exposed to A beta s, STAT3-dependent PKC delta expression triggers calpain2-mediated p35 cleavage into p25 to overactivate CDK5, thus leading to aberrant CCR, PUMA induction, caspase-3 cleavage, and ultimately apoptosis.