Stem cells for Alzheimer's?

Approach unlikely to yield cure for the disease, experts say, although some look to endogenous stem cell manipulation

By | June 11, 2004

The death of former US President Ronald Reagan Saturday (June 5) after a decade-long struggle with Alzheimer's disease—just a month after former First Lady Nancy Reagan spoke publicly for the first time in support of stem cell research—has firmly linked stem cells with the hope for an Alzheimer's cure in the public mind. But most in the field admit it's highly unlikely that a stem cell transplant could cure or even treat Alzheimer's.

"Alzheimer's is a tough target for this sort of thing because it is widespread and it involves so many different types of neurons," Donald L. Price, director of the Alzheimer's Research Center at Johns Hopkins, told The Scientist. "There are other diseases, like Parkinson's, which may be much more amenable to stem cell therapies."

It's a matter of taking a "very narrow view or a large view," said Sam Gandy, vice chair of the National Medical Scientific Advisory Council of the Alzheimer's Association and director of the Farber Institute for Neuroscience at Thomas Jefferson Hospital in Philadelphia. Lessons that can be learned from stem cell transplants for Parkinson's and other types of neurodegenerative disease will reveal a great deal about cell signaling and cell environment that could be applied in Alzheimer's, Gandy said.

Michael Shelanski, codirector of the Taub Institute for Research on Alzheimer's Disease at Columbia University, said he and his colleagues are developing drugs that would fight the degenerative disease by strengthening the synapse. Other groups are looking at ways to block gamma secretase and beta secretase. But over the long term, the stem cells already found in the brain offer the most intriguing potential, Shelanski and others said.

In fact, argued Mark Mehler, stem cells offer the only real hope for repairing the damage Alzheimer's does to brain cells and cellular connections built up over a lifetime.

"Our ability to repair damage to the nervous system has to be focused on not just giving back the cells that have died, but giving them back in a way that allows them to incorporate" into neural networks, Mehler, who directs the Institute for Brain Disorders and Neural Regeneration at the Albert Einstein College of Medicine in the Bronx, told The Scientist. "We have to supply them in the way that they were originally generated during development through activation and maturation of endogenous adult stem cells from brain regions adjacent to the sites of irrevocable cell injury and death."

Over the past 2 years, Mehler and his colleagues have found increasing evidence that the process that leads to cell death in Alzheimer's actually begins during early embryonic development, suggesting that such vulnerable cells could be repaired with gene therapy or even replaced by stem cells.

The former first lady's May 9 speech was her first public statement on stem cell research, although her views have been known for some time. The day before Reagan's death, a bipartisan group of 58 senators sent a letter to President Bush urging him to allow federal funds for research on donated surplus embryos created by in vitro fertilization. A group of congressmen sent a similar letter to the president this April, and received what some considered a promising response from NIH Director Elias Zerhouni.

If the wave of support driven by Reagan's death does lead to a shift in Bush Administration policy, "it would be a terrific boon to the field" of Alzheimer's research, said Fred Gage, professor in the Laboratory of Genetics at the Salk Institute in San Diego. Embryonic stem cells could be engineered to express the genetic defects known to lead to Alzheimer's, he said, which would offer a molecular and cellular window into the course of the disease and could also be used to screen compounds.

Using stem cells to replace a particular type of neuron "is something that should be kept on the horizon," said Gage, "but as an immediate application is hard to fathom."

A researcher who has used stem cell transplants in mice with Alzheimer's-like memory loss to improve the animals' performance in a maze is more upbeat than most about the potential of stem cell transplants for human disease. "I do believe stem cells can do many things for Alzheimer's," Kiminobu Sugaya, a professor at the University of Central Florida, told The Scientist.

One major hurdle, according to Sugaya, would be to downregulate the production of amyloid precursor protein in the brain before transplanting stem cells. Sugaya has done research suggesting that the protein has some physiological function in the normal brain, so he is reluctant to block it entirely. Then, he said, researchers could work toward using stem cells to replace the basal forebrain cholinergic cells that are the first to die in Alzheimer's. "It could be difficult, but I think we can figure out how to make it happen," Sugaya said. Also, he noted, it would be "easy" to replace the intramural cells in the cortex that degenerate in Alzheimer's with stem cells.

Though most in the field see this strategy as unrealistic, "one always hopes to be surprised," said Price.

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