Phosphorylated amyloid-beta: the toxic intermediate in alzheimer's disease neurodegeneration.

Abstract

Phosphorylated Amyloid-beta (Abeta) was identified in Alzheimer's disease (AD) brain. Using an anti-sense peptide approach the human cyclin-dependent kinase-1 (CDK-1) was identified as being responsible for Abeta phosphorylation. The phosphorylated Abeta peptide showed increased neurotoxicity and reduced ability to form Congo red-positive fibrils. Mutation of the serine 26 residue and inhibition of Abeta phosphorylation by the CDK-1 inhibitor olomoucine prevented Abeta toxicity, suggesting that the phosphorylated Abeta peptide represents a toxic intermediate. Cannabinoids prevented phosphorylated Abeta toxicity. The results from this study suggest that Abeta phosphorylation could play a role in AD pathology and represent a novel therapeutic target.