Abnormal proteins that form globs and restrict cognitive thinking, learning and memory problems in Alzheimer’s patients are mostly made up of beta-amyloid peptide. By understanding how they form, and how they affect brain function, researchers can move forward to improve the diagnosis and treatment of dementia patients.
A research team at Sanford-Burnham Medical Research Institute, led by Stuart A. Lipton, M.D., Ph.D., published online in the August 15 edition of Proceedings of the National Academy of Sciences, results of a study on the connections that mediate communication between nerve cells. 
The team found that the driving force behind beta-amyloids leading to the destruction of synapses (the connections between nerve cells) is a chemical medication call Cdk5. Cdk5 is an enzyme known to play a role in normal neuronal survival and migration. The researchers found altered forms of Cdk5 present in human brains with Alzheimer’s, but not in normal brains. Dr. Lipton and colleagues found that beta-amyloid peptides, the hallmark of Alzheimer’s disease, trigger Cdk5 modification by a chemical process called S-nitrosylation. Nitric oxide (NO) is attached to the enzyme, producing SNO-Cdk5 (the altered form of Cdk5), and disrupting its normal activity in this reaction. This would suggest that 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,” said Dr. Lipton, professor and director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging and Stem Cell Research Center.
In the current study, a new function of Cdk5 is shown – the ability to transfer NO from one protein to another. Cdk5 was only previously known to influence the function of other proteins by tagging them with phosphate groups in a process known as phosphorylation. This study found that the addition of NO puts Cdk5 into overdrive and allows it to also S-nitrosylate other proteins, in this case Drp1 on mitochondria. Most notably, the transfer of NO from SNO-Cdk5 to Drp1 triggers the loss of synapses, the part of a nerve cell that transmits electrochemical signals to other nerve cells. The degree of cognitive decline in Alzheimer’s patients is known to correspond to the loss synapses.
To go a step further, the team compared the brain tissue from healthy people and from Alzheimer’s disease patients and found SNO-Cdk5 was dramatically elevated in human brains with Alzheimer’s disease. “Our experiments using human brain tissue from patients with Alzheimer’s disease give this finding clear clinical relevance,” Dr. Lipton said. “SNO-Cdk5 could provide a new target for treating this devastating condition.”
Alzheimer’s is the 7th leading cause of death in the United States, and affects as many as 5.3 million Americans. Each year more studies are concluded to help put the puzzle together as to what pieces make up the Alzheimer’s puzzle. This is just another positive finding that may soon lead to the answers needed to fight, and maybe even cure, the disease.
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.
From the desk of Ron White, 2 Time USA Memory Champion
Sources:
Science Daily – Enzyme Found Disrupting Nerve Cell Communication in Alzheimer’s Disease : http://www.sciencedaily.com/releases/2011/08/110815152033.htm