| First Author | Sadleir KR | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 10 | Pages | 7224-35 |
| PubMed ID | 22223639 | Mgi Jnum | J:182773 |
| Mgi Id | MGI:5316563 | Doi | 10.1074/jbc.M111.333914 |
| Citation | Sadleir KR, et al. (2012) Cdk5 protein inhibition and Abeta42 increase BACE1 protein level in primary neurons by a post-transcriptional mechanism: implications of CDK5 as a therapeutic target for Alzheimer disease. J Biol Chem 287(10):7224-35 |
| abstractText | The beta-secretase enzyme BACE1 initiates production of the amyloid-beta (Abeta) peptide that comprises plaques in Alzheimer disease (AD) brain. BACE1 levels are increased in AD, potentially accelerating Abeta 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 Abeta42 oligomers had increased BACE1 level and p25:p35 ratio. Surprisingly, the Abeta42-induced BACE1 elevation was not blocked by Cdk5 inhibitors CP68130 and roscovitine, and instead the BACE1 level was increased greater than with Abeta42 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 Abeta42-induced BACE1 increase. Further experiments suggested that the Abeta42-induced BACE1 elevation was the result of a post-transcriptional mechanism. We conclude that Abeta42 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. |
