Regulation of Alzheimer's disease amyloid-beta formation by casein kinase I.
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.
Flajolet
Marc
M
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
He
Gen
G
Heiman
Myriam
M
Lin
Angie
A
Nairn
Angus C
AC
Greengard
Paul
P
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D047389:Casein Kinase I / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism; D051381:Rats
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D047389:Casein Kinase I