CDK5 Participates in Amyloid-β Production by Regulating PPARγ Phosphorylation in Primary Rat Hippocampal Neurons.

Cyclin-dependent kinase 5 (CDK5) in adipose tissue mediates peroxisome proliferator-activated receptor gamma (PPAR gamma) phosphorylation at Ser273 to inhibit its activity, causing PPAR gamma target gene expression changes. Among these, insulin-degrading enzyme (IDE) degrades amyloid-beta peptide (A beta), the core pathological product of Alzheimer's disease (AD), whereas beta-amyloid cleavage enzyme 1 (BACE1) hydrolyzes amyloid-beta protein precursor (A beta PP). Therefore, we speculated that CDK5 activity in the brain might participate in A beta production, thereby functioning as a key molecule in AD pathogenesis. To confirm this hypothesis, we transduced primary rat hippocampal neurons using CDK5-expressing lentiviral vectors. CDK5 overexpression increased PPAR gamma Ser273 phosphorylation, decreased IDE expression, increased BACE1 and A beta PP expression, increased A beta levels, and induced neuronal apoptosis. The CDK5 inhibitor roscovitine effectively reversed these CDK5 overexpression-mediated effects. Moreover, silencing of the Cdk5 gene via CDK5 shRNA-expressing lentiviral vectors in primary hippocampal neurons did not exert any protective effect against normal neuronal apoptosis, nor were significant effects observed on A beta levels, PPAR gamma phosphorylation, or PPAR gamma target gene expression in the cells. However, Cdk5 gene silencing exhibited a neuroprotective effect in the A beta-induced AD neuron model by effectively inhibiting the A beta-induced neuronal apoptosis, PPAR gamma phosphorylation, PPAR gamma expression downregulation, and PPAR gamma target gene expression changes, and reducing A beta levels. In conclusion, this study demonstrated that CDK5 played an important role in the pathogenesis of AD. Specifically, CDK5 participated in A beta production by regulating PPAR gamma phosphorylation. Targeted therapy against CDK5 could effectively reduce and reverse the neurotoxic effects of A beta and may represent a novel approach for AD treatment.