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...  Read more

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:
1. 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. Abstract

2. 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. Abstract

View all comments by Virgil Muresan
View all comments by Zoia Muresan

Bart De Strooper and his collaborators have characterized a microRNA cluster (miR29a/b-1) that is significantly and specifically downregulated in AD patients. miRNAs are extremely important regulators of gene expression that modulate both translation efficiency and stability of their target mRNAs. Importantly, the miRNA studied by De Strooper's group regulates the β-secretase BACE1. Downregulation of the miRNA cluster correlates with increased expression of BACE1 in AD patients, as well as during development and in primary cells. BACE1 mRNA is apparently not destabilized, indicating that in this case the miRNA controls the translation of the mRNA. If this control is lost, due to a decrease of miRNA expression, an excess of BACE1 is expressed, which will increase the malign processing of APP to form the AD-causing Aβ peptide.

First, this work further establishes BACE1 as a causative agent and hence drug target in AD. In this respect, it is also interesting that this effect is specific to AD patients and not seen in other forms of dementia. Second, this work, together with a...  Read more

Bart De Strooper and his collaborators have characterized a microRNA cluster (miR29a/b-1) that is significantly and specifically downregulated in AD patients. miRNAs are extremely important regulators of gene expression that modulate both translation efficiency and stability of their target mRNAs. Importantly, the miRNA studied by De Strooper's group regulates the β-secretase BACE1. Downregulation of the miRNA cluster correlates with increased expression of BACE1 in AD patients, as well as during development and in primary cells. BACE1 mRNA is apparently not destabilized, indicating that in this case the miRNA controls the translation of the mRNA. If this control is lost, due to a decrease of miRNA expression, an excess of BACE1 is expressed, which will increase the malign processing of APP to form the AD-causing Aβ peptide.

First, this work further establishes BACE1 as a causative agent and hence drug target in AD. In this respect, it is also interesting that this effect is specific to AD patients and not seen in other forms of dementia. Second, this work, together with a parallel study published almost at the same time (Wang et al., 2008), for the first time associates a dysregulation of miRNAs with AD development in humans.

Gene regulation by miRNAs is still a new and poorly understood field, and to have such a strong link to an important human pathology will certainly encourage further studies into the topic.

View all comments by Claudia Bagni

An excellent piece of work by Sebastien, Bart, and colleagues. This study underscores the role of BACE elevation in late-onset AD (LOAD).

This study from Bart's group and the recent work from Karen Duff's group on Cdk5's role in BACE transcription (Wen et al., 2008) now show that BACE levels could be regulated by distinct mechanisms acting either at the level of translation or transcription. Upregulation of BACE, either in terms of the enzymatic activity or protein levels, is clearly a risk for LOAD. Hence, understanding the mechanisms by which BACE is upregulated is crucial for AD etiology and also for therapy.

Bob Vassar's results on stress-induced eIF2a phosphorylation causing an increase in BACE levels also come timely [see ARF related Keystone story]. It would be interesting to find mechanisms that cause this eIF2a phosphorylation-induced switch to specific translation. Since cellular stress regulates miRNA levels, it would be interesting to see if there is...  Read more

An excellent piece of work by Sebastien, Bart, and colleagues. This study underscores the role of BACE elevation in late-onset AD (LOAD).

This study from Bart's group and the recent work from Karen Duff's group on Cdk5's role in BACE transcription (Wen et al., 2008) now show that BACE levels could be regulated by distinct mechanisms acting either at the level of translation or transcription. Upregulation of BACE, either in terms of the enzymatic activity or protein levels, is clearly a risk for LOAD. Hence, understanding the mechanisms by which BACE is upregulated is crucial for AD etiology and also for therapy.

Bob Vassar's results on stress-induced eIF2a phosphorylation causing an increase in BACE levels also come timely [see ARF related Keystone story]. It would be interesting to find mechanisms that cause this eIF2a phosphorylation-induced switch to specific translation. Since cellular stress regulates miRNA levels, it would be interesting to see if there is some stress-miRNA-BACE connection here. It would also be fascinating to see how aging, inflammation, or other factors that influence the risk for LOAD also influence the downregulation of these miRNAs.

View all comments by Lawrence Rajendran