Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marié I, Maurin T, Wang L, Figueroa H, Herman M, Krishnamurthy P, Liu L, Planel E, Lau LF, Lahiri DK, Duff K. Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008 Mar 13;57(5):680-90. PubMed.

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  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.

    References:

    Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marié I, Maurin T, Wang L, Figueroa H, Herman M, Krishnamurthy P, Liu L, Planel E, Lau LF, Lahiri DK, Duff K. Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008 Mar 13;57(5):680-90. PubMed.

    Muresan Z, Muresan V. 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.

    View all comments by Virgil Muresan

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