Age-related dementia is a common problem when we age. Neurons in the brain die and neural pathways become corrupted, and we forget things and lose the ability to perform everyday tasks. Can stem cell treatments reverse cognitive decline?
Perhaps they can. Yun-Bae Kim and Seung U. Kim from the Chungbuk National University College of Veterinary Medicine, in Cheongju, South Korea, and the Division of Neurology at the University of British Columbia Hospital, Vancouver, BC, Canada, have published a couple of papers that use neural stem cells engineered to make the neurotransmitter acetylcholine to treat rodents that have cognitive deficiencies. The results are surprising and hopeful.
Neurotransmitters are small molecules neurons release to talk to each other. Almost a century ago, physicians noticed that patients who took a drug called scopolamine failed to remember certain event after taking the drug. scopolamine is commonly used to treat motion sickness, and if any of you have ever been on board a cruise ship and experienced sea sickness, you were probably prescribed a scopolamine patch. scopolamine works by blocking the neurotransmitter acetylcholine and the fact that scopolamine takers (mind you at much higher concentrations than those used to relieve sea sickness) had memory lapses led neurologists to postulate that acetylcholine plays a role in learning and memory.
The role of acetylcholine in learning and memory has led to the development of treatments for Alzheimer’s disease patients in the form of drugs that increase the effectiveness of endogenous acetylcholine by decreasing its breakdown. These drugs, donepezil (Aricept) and rivastigmine (Exelon), are inhibitors of an enzyme called acetylcholine esterase. This enzyme degrades acetylcholine, thus effectively raising the internal levels of acetylcholine and increasing its activity. These two drugs improve the memory of patients with age-related dementia or the early stages of Alzheimer’s disease (AD).
To that end, Yun-Bae Kim and Seung U. Kim and others have engineered neural stem cells to overproduce and enzyme that synthesizes acetylcholine (choline acetyltransferase). The overproduction of this enzyme by these neural stem cells causes them to overproduce acetylcholine. Implantation of these acetylcholine-overproducing neural stem cells into the brains of laboratory animals that show cognitive declines should provide an excellent indication if such an experiment is feasible in human patients.
In their first experiment, Kim’s research team fed rats a drug that kills off neurons that use acetylcholine. When given to rodents, this drug (ethylcholine mustard aziridinium ion or AF64A) produces memory problems that have some similarities to what is observed in patients with Alzheimer’s disease. Then they transplanted human neural stem cells that made overexpressed acetylcholine into the brains of these memory-challenged rats. Remarkably, the rats with the implanted neural stem cells that overexpressed acetylcholine completely recovered their learning and memory function, and had elevated levels of acetylcholine in their cerebrospinal fluid (CSF). When the brains of these animals were examined in postmortem examinations, they discovered that the human neural stem cells had migrated to various brain regions including cerebral cortex, hippocampus, striatum and septum, and differentiated into neurons and star-like support cells known as astrocytes. This study shows that brain transplantation of human NSCs that over-expressing acetylcholine improved the complex learning and memory problems in rats with a drug-induced type of Alzheimer’s disease.
In their second paper, the Kim research group did a very similar experiment, but they used a different drug to induce learning and memory problems (kainic acid). The drug was injected directly into the part of the brain known to play a role in learning and memory, the hippocampus. This procedure generated animals with profound learning and memory problems.
The engineered human neural stem cells were injected into the ventricles of the brain, and the cells not only found their way into the brain, but they migrated directly to the damaged area of the brain. The neural stem cells differentiated into neurons and astrocytes and restored, to some degree, the learning and memory defects in these animals.
Taken together, these experiments show that engineered neural stem cells can find their way to the damaged areas of the brain and reconstitute those damaged pathways, at least to some degree. Also, these new neural pathways restore at least some learning and memory defects that result from the death of the acetylcholine-using neurons. These experiments are crying out for more work and confirmation by other groups.
See Park D., et al., Cell Transplant. 2012;21(1):365-71 & Park D., et al., Exp Neurol. 2012; 234(2):521-6