Scientists Use Stem Cells, Skin Cells to Create Brain Cells Lost to Alzheimer's

FRIDAY March 4, 2011 -- In what experts are calling a significant step forward in Alzheimer's research, scientists have for the first time turned human embryonic stem cells and a form of human skin cell into a type of brain cell that's lost to Alzheimer's disease.

The disease-induced destruction of these cells, which are called "basal forebrain cholinergic" (BFC) neurons, is key to the progression of Alzheimer's. Their death, say researchers, leads to memory-retrieval problems, one of the most disabling aspects of the illness. Similarly, BFC loss also impairs spatial learning.

But the new study suggests that scientists could someday create a virtually unlimited supply of these neurons in a laboratory setting. This should help deepen scientific research into Alzheimer's by allowing the scientists to rapidly test thousands of different drugs on the neurons to see which drugs keep them alive under various conditions -- research that could enhance the development of new drugs against the disease.

Much further in the future, but possible, is the notion of transplanting healthy, lab-grown neurons back into the brains of Alzheimer's patients as treatment.

"I like to be very cautious, and not tell people that now we have a treatment for Alzheimer's," noted co-author Dr. John A. Kessler from the department of neurology at Northwestern University's Feinberg School of Medicine in Chicago. "But now we can actually make human cells that are exactly the kind of groups of neurons that play a central role in memory and seem to die very early on in the onset of Alzheimer's."

"Now, Alzheimer's is a disease that's not going to be treated and cured by any one magic bullet," he cautioned. "But I can tell you that without actually having these cells available we can't even begin to think about a treatment. So what this does is enable us to start trying to find ways to help these patients have a more normal ability to process information, access memories, and make new memories."

The Northwestern team of scientists report on their research in the March 4 issue of Stem Cells. The work was funded by the U.S. National Institutes of Health.

The kind of memory impairment that affects Alzheimer's patients is not, the team notes, a question of the loss of memories themselves, but rather the loss of the capacity to access those memories. It is this retrieval process, as well as the process of generating fresh memories, that the relatively small group of BFC neurons facilitate as they work away in the hippocampus region of the brain.

When BFC function is impaired, so is memory.

The loss of his grandfather to Alzheimer's spurred study lead author Christopher Bissonnette, a former doctoral student in neurology at Northwestern, to search for new ways of fighting the disease. That involved figuring out how to coax embryonic stem cells -- which have the theoretical potential to develop into any kind of cell -- into becoming BFC replacement cells.

Once they crossed that hurdle, Bissonnette's team had to ensure that the human neural material they'd coaxed into being was stable enough to survive for a minimum of 20 days under laboratory conditions.

After much trial and error, the investigators were able to do so. In fact, once a sufficiently nurturing tissue-culture environment was fashioned, the researchers found that their lab-induced BFC replacement cells could live "indefinitely."

Work with mice whose brains were implanted with the replacement cells demonstrated that the new neural material sent out connecting fibers to the hippocampus and appeared to function in the same way as the mice's natural BFC cells.

In another experiment, the team developed a second means of creating BFC replacement cells. This time they used human skins cells rather than embryonic stem cells as their primary material.

Skin cells were obtained from three difference sources: Alzheimer's patients, healthy patients deemed to be at risk for Alzheimer's, and healthy patients with no elevated risk or family history of the disease.

In turn, in the lab the authors were able to coax these cells into first becoming human stem cells, otherwise known as "induced pluripotent stem cells." From there, the cells could then be fashioned into BFC replacement cells.

"Now, most of the data in our paper comes from our work with human embryonic stem cells," stressed Kessler. "But of course, there's probably nobody alive on this planet that isn't aware of the ethical issues surrounding this process. So the advantage of using skin cells as the source is that this would bypass that question."

"Secondly, ideally we would like to have neurons that we might transfer to people to be perfectly matched with the patient," he added. "So that the immune system doesn't try to reject those cells. Now, if you were take skin cells from the patients themselves and then use them to actually create the neurons that you'll be transferring back into them, then they would have the same DNA as the patient and be a perfect match. So that's another reason this is a promising approach."

"However, the caveat is that cells that are made from skin cells are very similar to embryonic stem cells, but they are not identical to them," Kessler noted. "Before we can even think about using these sorts of 'induced' cells for any kind of treatment, we will have to overcome a whole host of problematic issues. So clearly, there is a lot more work to be done."

William Thies, chief medical and scientific officer with the Alzheimer's Association in Chicago, agreed that there's still much work to be done.

He stressed that the current lab work should be viewed as early, "basic science" rather than heralding any new treatment.

"We're cautiously optimistic about the finding," he said. "This may be fairly important. But we need to report the fact that it's happened and could be important, and keep that separate from the idea that you will be able to stop by your family physician and get a stem cell transplant in the next six weeks."

"This piece of work is really looking at a method to generate a large number of a certain kind of brain cell that we know is involved in Alzheimer's disease," Thies noted. "And the generation of those cells really opens up the possibility that we will be able to much more rapidly test new therapies. That would be something that could have an impact in the next couple of years."

But he cautioned against any short-term anticipation along the lines of stem cell transplant treatments. "That," he said, "is maybe 50 to 100 years away."

Posted: March 2011


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