Enzyme Could Be Reason for Neuron Communication Problem

Alzheimer’s is the 7th leading cause of death in the United States, affecting as many as 5.3 million Americans. Each new study of the disease helps to put the Alzheimer’s puzzle together that may soon lead to the answers needed to fight, and maybe even cure, the disease.

Researcher sat Sanford-Burnham Medical Research Institute have found that abnormal proteins that form globs, similar to fat buildup, cause a communication problem by restricting mental functions, learning, memory and cognitive skills, in dementia and Alzheimer’s disease patients. These globs are made up of a substance called beta-amyloid peptide.

The research team, led by Stuart A. Lipton, M.D., Ph.D., published their report online in the August 15, 2011 edition of Proceedings of the National Academy of Sciences. The results of a study showed the connections that take place between cells. They found that the driving force behind beta-amyloids destroying the synapses (the connections between nerve cells) is a chemical medication call Cdk5.

Cdk5 is an enzyme that has been shown to play a part in the survival of normal neuron (brain cell) activity and movement. The researchers found that the brains of human Alzheimer’s patients had altered forms of Cdk5 present, while those with normal brains did not.  Lipton and colleagues found that beta-amyloid peptides, the hallmark of Alzheimer’s disease, trigger the Cdk5 enzymes to undergo a chemical process called S-nitrosylation modifies the enzymes. In the process, Nitric oxide (NO) attaches to the enzyme and produces SNO-Cdk5 (the altered form of Cdk5), disrupting its normal activity reaction. This would suggest to researchers that the use of SNO-Cdk5 could be the next target for therapies for Alzheimer’s patients.

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,” says Lipton, professor and director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging and Stem Cell Research Center.

A new function of Cdk5 is shown in the current study – the ability to transfer nitric oxide from one protein to another. Previously, Cdk5 was only known to influence the function of other proteins, in a process known as phosphorylation, by tagging them with phosphate groups. This study found that by adding NO it puts the Cdk5 enzyme into overdrive and allows it to undergo the chemical change of S-nitrosylate other proteins – in this case Drp1 on mitochondria.

Of most importance they found that the transfer of NO from SNO-Cdk5 to Drp1 triggers the loss of electrochemical signal transmission (synapse) to other nerve cells. The amount of mental and cognitive functions in dementia and Alzheimer’s patients is known to the loss of these connections.

To take it a step further, the team compared the brain tissue from healthy people and from Alzheimer’s disease patients and found a dramatic rise in SNO-Cdk5 in the brains of Alzheimer’s patients. “Our experiments using human brain tissue from patients with Alzheimer’s disease give this finding clear clinical relevance,” Lipton said. SNO-Cdk5 could provide a new target for treating this devastating condition.

This study was funded by the National Institutes of Health (NIH). Co-authors include Jing Qu, Tomohiro Nakamura, Gang Cao, Emily A. Holland, Scott R. McKercher, and Stuart A. Lipton, all located at Sanford-Burnham in La Jolla, Calif. Dr. Lipton is also a neurologist who sees Alzheimer’s disease patients in his own clinical practice, and is credited with characterizing and developing memantine (Namenda ®), the latest FDA-approved drug for Alzheimer’s disease.

About the author:

Ron White is a two-time U.S.A. Memory Champion and memory training expert. As a memory keynote speaker he travels the world to speak before large groups or small company seminars, demonstrating his memory skills and teaching others how to improve their memory, and how important a good memory is in all phases of your life. His CDs and memory products are also available online at BrainAthlete.com.


Science Daily – Enzyme Found Disrupting Nerve Cell Communication in Alzheimer’s Disease : http://www.sciencedaily.com/releases/2011/08/110815152033.htm

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