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

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This fly paper catches genetic evidence that Rac inhibition slows memory decay, constitutively increased Rac activation accelerates memory decay, and that cofilin hyperactivation gives rise to the same phenotype as seen with Rac inhibition. The authors conclude that the “Rac-regulated PAK/LIMK/cofilin pathway might be critical in influencing memory decay.” The specificity for Rac activation defects in an active forgetting process relevant to stronger longer-term memory with repetitive learning is novel and interesting. To the extent that these observations can be generalized to mammals, they may relate to the acute and chronic soluble Aβ oligomer-induced dysregulation of Rac/PAK/LIMK1/cofilin signaling (Zhao et al 2006., Ma et al., 2008, Gureviciene et al., and other refs) with LTP deficits and enhanced LTD (Li et al., 2009) and synapse loss (Freir et al., 2010). Conversely, memory consolidation is also impaired along with enhanced LTP and reduced LTP when PAK is selectively genetically inhibited in forebrain (Hayashi et al., 2004).

References:
Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009 Jun 25;62(6):788-801. Abstract

Ma QL, Yang F, Calon F, Ubeda OJ, Hansen JE, Weisbart RH, Beech W, Frautschy SA, Cole GM. p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis. J Biol Chem. 2008 May 16;283(20):14132-43. Abstract

Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci. 2006 Feb;9(2):234-42. Abstract

ML, Choi SY, Rao BS, Jung HY, Lee HK, Zhang D, Chattarji S, Kirkwood A, Tonegawa S. Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron. 2004 Jun 10;42(5):773-87. Abstract

Gureviciene I, Ikonen S, Gurevicius K, Sarkaki A, van Groen T, Pussinen R, Ylinen A, Tanila H. Normal induction but accelerated decay of LTP in APP + PS1 transgenic mice. Neurobiol Dis. 2004 Mar;15(2):188-95. Abstract

Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G. Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300. Abstract

Freir DB, Fedriani R, Scully D, Smith IM, Selkoe DJ, Walsh DM, Regan CM. Abeta oligomers inhibit synapse remodelling necessary for memory consolidation. Neurobiol Aging. 2010 Jan 22. Abstract

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