The cyclin-dependent kinase Cdk5 has diverse functions in the brain, and has been implicated in Alzheimer disease in multiple contexts. The Cdk5 activator p25 has been reported to be elevated in AD brain and causes neurodegeneration in mice (see ARF related news story). The kinase phosphorylates tau (see ARF related news story) and contributes to Aβ production (see ARF related news story) and dendritic spine loss (see ARF related news story).

Now, Karen Duff and colleagues at Columbia University in New York have identified another potentially pathologic action of Cdk5. In the March 13 Neuron, they show that the p25-mediated activation of Cdk5 can increase production of Aβ via transcriptional induction of β-secretase 1 (BACE1) gene expression. Treating p25 transgenic mice with a Cdk5 kinase inhibitor reversed the elevation of BACE and reduced amyloid production, suggesting that the kinase could be a target for an amyloid-lowering strategy.

To gauge the effect of Cdk5 activation on BACE, first authors Yi Wen and W. Haung Yu initially looked at cells transfected with an inducible p25 construct. They found that the cells had abundant BACE1 protein and activity, and displayed enhanced β cleavage of APP. The cells displayed a sixfold induction of BACE1 mRNA, and promoter mapping revealed that transcriptional regulation localized to a region containing binding sites for the Cdk5 substrate and transcription factor STAT3. In cells overexpressing p25, STAT3 was phosphorylated and activated. Chromatin immunoprecipitation experiments showed that STAT3 interacts with the BACE1 promoter.

Together, the data point to a role for STAT3 in regulating BACE1 transcription in vitro. In vivo support for that idea came from mice that overexpress p25, where the investigators found both STAT3 phosphorylation and BACE1 elevation. Conversely, embryos from Cdk5 knockout mice had a reduction in both STAT3 phosphorylation (by 70 percent) and BACE1 elevation (by 30 percent). Likewise, brain tissue from mice with a targeted mutation of STAT3 that prevented its activation showed a 30 percent reduction in BACE1 levels.

Finally, treatment of young p25 mice with a Cdk5 inhibitor led to a significant reduction in BACE1 mRNA and protein, and in phosphorylated STAT3. The inhibitor-treated mice also produced less Aβ. Similar results were seen in adult p25 mice. In human APP-expressing mice, p25 increased the β processing of APP, but did not result in a statistically significant difference in plaque load, although Aβ levels showed a trend to increase.

The results agree with previous work in an inducible p25 transgenic mouse, where boosting Cdk5 activity induces Aβ production (Cruz et al., 2006). However, Duff told ARF, she does not know exactly how the findings might relate to AD. While there is some published data indicating that Cdk5 is increased in AD brain, in most cases where BACE mRNA has been checked, it is not elevated, she said. However, BACE protein and its activity are increased in AD brain, but the mechanism of how that occurs is unknown.

On the other hand, the regulation of BACE by p25 might explain the increased incidence of AD after stroke, Duff says. “The question of whether Cdk5 is aberrantly activated in AD is controversial, but published data suggest that the p25/Cdk5 pathway is activated in ischemia,” she explained. Other data point to hypoxia as an activator of STAT3 and BACE1 transcription, suggesting that the Cdk5 pathway could initiate or exacerbate Aβ pathology in brain regions affected by stroke.

The finding that aberrant p25/Cdk5 activity enhances Aβ accumulation also raises the possibility that inhibitors of the kinase could be candidates for therapeutic development. “Anything that affects BACE activity is important to try for its effects on pathogenesis,” Duff said. However, there are few Cdk5 inhibitors, specific or otherwise, available for testing thus far. The best-known Cdk5 inhibitor, roscovitine, does not cross the blood-brain barrier. The inhibitor used in the current study does, but is highly toxic, and Duff reports that it is lethal when given to mice for more than a week.—Pat McCaffrey


  1. We would like to comment on the interesting article by Wen et al. [1] on triggering BACE1 gene expression through activation of Cdk5, a pathway that leads to increased production of Aβ. In her comments to ARF, the senior author Karen Duff correctly states that one “does not know exactly how the findings might relate to AD,” since there is still little evidence that BACE1 mRNA is elevated in AD brains.

    We have recently reported that overexpression of APP in cultured neuronal cells may lead to neurodegeneration, a process that is accompanied by hyperphosphorylation of APP (at Thr668; numbering for APP695) and localization of the phosphorylated APP to endosomes [2]. Interestingly, while in differentiating neurons APP is phosphorylated at Thr668 by JNK, in these degenerating neurons the same residue is phosphorylated by Cdk5. In immunocytochemistry, Cdk5 and its activator (likely p25; our antibodies did not discern between p25 and p35) appeared to be slightly elevated, but this may be also a result of mislocalization in addition to increased protein levels. At the time of publication, we interpreted these results as indicative of a mechanism for eliminating excess APP, when APP levels are increased. APP processing via BACE1 likely occurs in endosomal compartments, where this enzyme is fully active.

    Based on the results of Wen et al., we now speculate that the increased Cdk5 activity in these degenerating neurons may have also caused—through transcriptional control—an increase in BACE1 levels (and activity), leading thus to an increased processing of the endosomally targeted APP. Such a mechanism may account for the elevated levels of phosphorylated CTFs and, upon γ-secretase cleavage, of Aβ. It would be interesting to find out what causes the activation of Cdk5 under these conditions.

    While the experimental system used by us (i.e., APP overexpressing cells) [2] may not be directly relevant to AD (other than to some early onset cases with APP locus duplication), it is certainly relevant to Down syndrome. Therefore, the mechanism described by Wen et al. may also apply to the condition in Down syndrome. In any case, it appears that Cdk5 activation has pleiotropic effects, which may lead to disease in multiple ways.


    . Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008 Mar 13;57(5):680-90. PubMed.

    . The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration. Mol Biol Cell. 2007 Oct;18(10):3835-44. PubMed.

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News Citations

  1. Enzyme Essential to Brain Development Found to Hyperphosphorylate Tau, Kill Neurons
  2. Aiding and Abetting, Hyperactive CDK5 Gives Mouse Tangles
  3. Tangles, Neurodegeneration, Plaques—p25 Does it All
  4. What Drives Dendritic Spine Loss? Study Taps Cdk5

Paper Citations

  1. . p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J Neurosci. 2006 Oct 11;26(41):10536-41. PubMed.

Further Reading


  1. . Cdk5 deregulation in the pathogenesis of Alzheimer's disease. Trends Mol Med. 2004 Sep;10(9):452-8. PubMed.
  2. . Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron. 2003 Oct 30;40(3):471-83. PubMed.

Primary Papers

  1. . Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008 Mar 13;57(5):680-90. PubMed.