Phosphorylated amyloid-beta: the toxic intermediate in alzheimer's disease neurodegeneration.
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.
Milton
Nathaniel G N
NG
Department of Clinical Neurosciences, Royal Free & University College Medical School, University College London, London, UK.
D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007701:Kinetin; D009410:Nerve Degeneration / Q000473:pathology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010766:Phosphorylation; D011687:Purines / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D011687:Purines; C090046:olomoucine; D018844:Cyclin-Dependent Kinases; D007701:Kinetin