Regulation of Alzheimer's disease amyloid-beta formation.
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Alzheimer's disease (AD) is associated with accumulation of the neurotoxic peptide amyloid-beta, 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 CK1, 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 A peptide production. By using mammalian cells expressing the C-terminal fragment of APP, it was possible to demonstrate that CK1 inhibitors act at the level of -secretase cleavage. Importantly, Notch cleavage was not affected. Our results indicate that CK1 represents a therapeutic target for prevention of Abeta formation in AD.
Outhors analysis of consensus phosphorylation sites for CK1 conserved in mammalian proteins related to AD has revealed potential regulation of these proteins by CK1. Here we show that three different structurally unrelated, CK1-specific inhibitors, significantly reduce endogenous Abeta peptide production by selectively interfering with amyloid precursor protein (APP) gamma-cleavage. Conversely, overexpression of constitutively active CK1 leads to an increase of Abeta peptide production. This effect is specific for one of the brain CK1 isoforms (CK1). Importantly, Notch cleavage is not affected. Taken together, these results strongly suggest that CK1 represents an attractive target for development of novel therapies for the treatment of AD. PNAS | March 6, 2007 | vol. 104 | no. 10 | 4159-4164
Alzheimer's Donation
Donate Online Now
.
Alzheimer's disease (AD) is associated with accumulation of the neurotoxic peptide amyloid-beta, 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 CK1, 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 A peptide production. By using mammalian cells expressing the C-terminal fragment of APP, it was possible to demonstrate that CK1 inhibitors act at the level of -secretase cleavage. Importantly, Notch cleavage was not affected. Our results indicate that CK1 represents a therapeutic target for prevention of Abeta formation in AD.
Outhors analysis of consensus phosphorylation sites for CK1 conserved in mammalian proteins related to AD has revealed potential regulation of these proteins by CK1. Here we show that three different structurally unrelated, CK1-specific inhibitors, significantly reduce endogenous Abeta peptide production by selectively interfering with amyloid precursor protein (APP) gamma-cleavage. Conversely, overexpression of constitutively active CK1 leads to an increase of Abeta peptide production. This effect is specific for one of the brain CK1 isoforms (CK1). Importantly, Notch cleavage is not affected. Taken together, these results strongly suggest that CK1 represents an attractive target for development of novel therapies for the treatment of AD. PNAS | March 6, 2007 | vol. 104 | no. 10 | 4159-4164
posted by Valery Yermalitsky at
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