Protein Enzyme Implicated in Alzheimer’s Disease

March 31, 2012 § Leave a comment

Alzheimer’s disease is the seventh-leading cause of death in the United States. As many as 5.3 million Americans are living with Alzheimer’s disease. The disease is caused when abnormal proteins stick together, forming globules. These accumulations disrupt cognitive functions such as thinking, learning and memory. A better understanding of these beta-amyloid peptide proteins, in regards to how they form and how brain functions are affected by them, will greatly improve diagnosis and treatment of Alzheimer’s disease.

A research team at Sandford-Burnham Medical Research Institute, led by Stuart A. Lipton, MD. & Ph.D., found that these beta-amyloid proteins induce destruction of nerve synapses. These are the connections that meditate communication between nerve cells. The destruction of these synapses is driven by a chemical modification to an enzyme called Cdk5. These modified Cdk5 are common in the brains of Alzheimer’s disease patients, triggering damage to nerve cell connections, and are not found in normal human brains.

The results of Lipton’s research team were published online the week of August 15, 2012, in the Proceedings of the National Academy of Science of the USA, and they suggested that the altered enzyme, Cdk5, could be targeted for the development of new Alzheimer’s disease therapies.

Cdk5 is believes to be a part of the survival and migration of neurons. Modification of Cdk5 is triggered by a chemical process called S-nitrosylation. In this chemical reaction, nitric oxide (NO) is attached to Cdk5 enzymes, which then produces SNO-Cdk5. This alteration disrupts Cdk5’s normal activity.

Dr. Lipton explains, “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. The scenario disrupts communication between nerve cells, and thus memory and cognitive ability in Alzheimer’s disease.”

The study also revealed an unknown tertiary function performed by the Cdk5 enzyme. It has the ability to transfer NO from one protein to another. Until now, Cdk5 was only known to persuade the functions of other proteins by labelling them with phosphate groups, known as phosphorylation. The part of a nerve cell that transfers electrochemical signals to other nerve cells are called synapses. Loss of synapses corresponds with the degree of cognitive decline in Alzheimer’s disease.

This study shows that the addition of NO to Cdk5 send it into overdrive, causing it to S-nitrosylate other proteins – in this case, Drp1 on mitochondria. The loss of synapses is triggered by the transfer of NO from SNO-Cdk5 to Drp1.

To take the study further, the team compared SNO-Cdk5 levels in brain tissue from Alzheimer’s disease patients with that of healthy people. Patients with Alzheimer’s disease showed a significant elevation of SNO-Cdk5. SNO-Cdk5 may provide a new target for treating Alzheimer’s disease.


Heather Buschman, P. (2011, August 15). Study Finds Enzyme Disrupting Nerve Cell Communication in Alzheimer’s Disease. Retrieved from Neuroscience



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