The Pharmaceutical Journal
Vol 278 No 7443 p303
17 March 2007

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Potential new target for Alzheimer's disease identified

Researchers have identified a new therapeutic target — casein kinase 1 — that they say could lead to drugs that treat Alzheimer's disease without causing side effects (published online in Proceedings of the National Academy of Sciences, 26 February 2007).

Alzheimer’s disease is associated with accumulation of the neurotoxic peptide amyloid-beta, which is formed by the cleavage of amyloid precursor protein by the aspartyl protease BACE and gamma-secretase.

The researchers explain that major efforts to develop selective inhibitors of these enzymes have met with limited success. Most gamma-secretase inhibitors also inhibit Notch, a protein that is essential for normal development. The researchers have identified another protein, casein kinase 1 (CK1), which controls the regulation of these enzymes. Based on studies in mammalian cells, they show that three different CK1-specific inhibitors, which are structurally unrelated, significantly reduce endogenous amyloid-beta production by selectively interfering with APP gamma-cleavage. Under conditions in which inhibition of CK1 activity reduces beta-amyloid formation, no inhibition of Notch cleavage was observed, they say.

The researchers suggest that CK1 represents a potential therapeutic target for Alzheimer’s disease.