Cdk5 Protein Inhibition and Aβ42 Increase BACE1 Protein Level in Primary Neurons by a Post-transcriptional Mechanism IMPLICATIONS OF CDK5 AS A THERAPEUTIC TARGET FOR ALZHEIMER DISEASE

The beta-secretase enzyme BACE1 initiates production of the amyloid-beta (A beta) peptide that comprises plaques in Alzheimer disease (AD) brain. BACE1 levels are increased in AD, potentially accelerating A beta generation, but the mechanisms of BACE1 elevation are not fully understood. Cdk5/p25 has been implicated in neurodegeneration and BACE1 regulation, suggesting therapeutic Cdk5 inhibition for AD. In addition, caspase 3 has been implicated in BACE1 elevation. Here, we show that the Cdk5 level and p25:p35 ratio were elevated and correlated with BACE1 level in brains of AD patients and 5XFAD transgenic mice. Mouse primary cortical neurons treated with A beta 42 oligomers had increased BACE1 level and p25:p35 ratio. Surprisingly, the A beta 42-induced BACE1 elevation was not blocked by Cdk5 inhibitors CP68130 and roscovitine, and instead the BACE1 level was increased greater than with A beta 42 treatment alone. Moreover, Cdk5 inhibitors alone elevated BACE1 in a time-and dose-dependent manner that coincided with increased caspase 3 cleavage and decreased Cdk5 level. Caspase 3 inhibitor benzyloxycarbonyl-VAD failed to prevent the A beta 42-induced BACE1 increase. Further experiments suggested that the A beta 42-induced BACE1 elevation was the result of a post-transcriptional mechanism. We conclude that A beta 42 may increase the BACE1 level independently of either Cdk5 or caspase 3 and that Cdk5 inhibition for AD may cause BACE1 elevation, a potentially negative therapeutic outcome.