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Regulation of Alzheimer's disease amyloid-beta formation by casein kinase I.

Authors: Flajolet, M  He, G  Heiman, M  Lin, A  Nairn, AC  Greengard, P 
Citation: Flajolet M, etal., Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4159-64. Epub 2007 Feb 27.
Pubmed: (View Article at PubMed) PMID:17360493
DOI: Full-text: DOI:10.1073/pnas.0611236104

Alzheimer's disease (AD) is associated with accumulation of the neurotoxic peptide amyloid-beta (Abeta), which is produced by sequential cleavage of amyloid precursor protein (APP) by the aspartyl protease beta-secretase and the presenilin-dependent protease gamma-secretase. An increase of casein kinase 1 (CK1) expression has been described in the human AD brain. We show, by using in silico analysis, that APP, beta-secretase, and gamma-secretase subunits contain, in their intracellular regions, multiple CK1 consensus phosphorylation sites, many of which are conserved among human, rat, and mouse species. Overexpression of constitutively active CK1epsilon, one of the CK1 isoforms expressed in brain, leads to an increase in Abeta peptide production. Conversely, three structurally dissimilar CK1-specific inhibitors significantly reduced endogenous Abeta peptide production. By using mammalian cells expressing the beta C-terminal fragment of APP, it was possible to demonstrate that CK1 inhibitors act at the level of gamma-secretase cleavage. Importantly, Notch cleavage was not affected. Our results indicate that CK1 represents a therapeutic target for prevention of Abeta formation in AD.


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CRRD Object Information
CRRD ID: 10395238
Created: 2015-08-26
Species: All species
Last Modified: 2015-08-26
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.