The cause of Alzheimer’s disease can be traced back to sticky proteins made of beta-amyloid peptide. On this note, researchers from Sanford-Burnham Medical Research Institute (Sanford-Burnham), have unraveled an enzyme Cdk5 which if chemically altered invokes destruction of synapses by beta-amyloid.
The scientists found that this modified form of Cdk5 which is SNO-Cdk5, was apparently present in human Alzheimer’s disease brains, unlike their normal counterparts. Cdk5 is known to be an essential enzyme for natural neuronal survival and migration. As per this analysis, the team found that beta-amyloid peptides boost Cdk5 alteration by a chemical reaction called S-nitrosylation. This process involves nitric oxide (NO) attachment to the enzyme, to form SNO-Cdk5 and thus disturbing its usual action.
“After NO is attached to Cdk5, it then jumps like a ‘hot potato’ to another protein called Drp1, disrupting its function and fragmenting mitochondria, the energy powerhouse of nerve cells. When the mitochondria are damaged, the synapses, which normally require a lot of energy for their function, are destroyed. This scenario disrupts communication between nerve cells, and thus memory and cognitive ability in Alzheimer’s disease,” elaborated Dr. Lipton, professor and director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging and Stem Cell Research Center.
This research unfolds the transferring capability of Cdk5 which was not initially known. It apparently transfers NO from one protein to another. It was found that when NO is added, it gears Cdk5 to S-nitrosylate other proteins. This reaction involves Drp1 on mitochondria. Strikingly, transit of NO from SNO-Cdk5 to Drp1 accelerates the loss of synapses. The latter is a portion of the nerve cell that shifts electrochemical signals to other nerve cells. Loss of synapses is supposedly related to the cognitive decline in Alzheimer’s disease. Lipton concludes that this approach with SNO-Cdk5 is clinically relevant as it has been conducted using human brain tissue from Alzheimer’s disease patients. It could help in the development of potential therapies for this severe condition.
The findings are published online in the August 15 issue of the Proceedings of the National Academy of Sciences of the USA.