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Of mice and men: UCI scientists show that neural stem cells can rescue memory in mice with advanced Alzheimer's disease
IRVINE, Calif.—Scientists at the University of California in Irvine (UCI) say neural stem cells helped rescue memory in mice with Alzheimer's disease. The team successfully used injections of neural stem cells to repair damaged brain cells.
Frank LaFerla, director of UCI's Institute for Memory Impairments & Neurological Disorders, or UCI MIND, and co-author of the study that appeared recently in the Proceedings of the National Academy of Sciences, said that mice genetically engineered to have Alzheimer's performed markedly better on memory tests a month after mouse neural stem cells were injected into their brains. The stem cells secreted a protein that created more neural connections, improving cognitive function.
"Essentially, the cells were producing fertilizer for the brain," LaFerla says.
The findings also raise hopes for a potential treatment for the leading cause of elderly dementia that afflicts 5.3 million people in the United States.
"It gives new impetus to evaluate cell-based therapies as a potential treatment for Alzheimer's disease," Laferla says. "It is important to point out, that it may not necessarily be a cell that proves to be therapeutic but a factor identified from these studies. Certainly, our original study points to brain-derived neurotrophic factor (BDNF) as playing a benefical role, hence BDNF mimetics may be useful for treating Alzheimers disease."
Lead author Mathew Blurton-Jones, LaFerla and colleagues worked with older mice predisposed to develop brains lesions called plaques and tangles that are the hallmarks of Alzheimer's.
To learn how the stem cells worked, the scientists examined the mouse brains. To their surprise, they discovered that just 6 percent of the stem cells had turned into neurons. The majority became the other two main types of brain cells, astrocytes and oligodendrocytes. The stem cells didn't improve cognition by becoming new neurons, nor did they act by reducing the number of plaques and tangles.
Rather, the stem cells were found to have secreted a protein called BDNF. This caused existing tissue to sprout new neurites, strengthening and increasing the number of connections between neurons. When the team selectively reduced BDNF from the stem cells, the benefit was lost, providing strong evidence that BDNF is critical to the effect of stem cells on memory and neuronal function.
"If you look at Alzheimer's, it's not the plaques and tangles that correlate best with dementia; it's the loss of synapses—connections between neurons," Blurton-Jones says. "The neural stem cells were helping the brain form new synapses and nursing the injured neurons back to health."
Diseased mice injected directly with BDNF also improved cognitively but not as much as with the neural stem cells, which provided a more long-term and consistent supply of the protein.
LaFerla says the result gives scientists "a lot of hope that stem cells or a product from them, such as BDNF, will be a useful treatment for Alzheimer's."
LeFerla notes that the team was skeptical that stem cells would be effective simply because the Alzheimer brain contains damage to many regions.
"Initially, we thought that stem cells would lead to repair through a replacement model," he says. "Instead, we found that the stem cells were performing a nursing function, producing a neurotrophic factor, BDNF, which our studies pointed to as causing the improvement in memory. The fact that the stem cells were performing a nursing function in the AD brain suggests that one doesn't have to target them to multiple brain regions in order to see efficacy."
Although the experiment was only done on mice, the researchers are confident that the technique may one day be used on humans to restore memory lost during the late stages of Alzheimer's.
Whether the experiment can be replicated and the findings translated to human populations remains to be seen.
"We haven't yet evaluated the long term effects of the stem cell treatments in mice, but we are hopefully that it will allow for some reversal of cognitive function, not just stabilization," notes LeFerla. "These experiments will have to be done in order to make this conclusion."
The very next step for the scientists, according to LeFerla, is to evaluate different human stem cells to determine if they are capable of restoring function in the mouse.
"There are many human cell lines that are available and clinical application requires that we identify the appropriate line to develop and prepare under good manufacturing procedures," he notes. "There are many questions that remain to be addressed, such as whether the sex of the cell makes a difference, i.e., will implanting a male cell into a female brain matter, or whether the genotype of the cell is important—for example, ApoE4 is a risk factor for Alzheimer's disease, but if the best human cell harbors the ApoE4 alleles, will that matter?"
In April, LaFerla, Blurton-Jones and colleagues were awarded $3.6 million by the California Institute for Regenerative Medicine toward the development of an Alzheimer's therapy involving human neural stem cells.
In addition to LaFerla and Blurton-Jones, Masashi Kitazawa, Hilda Martinez-Coria, Nicholas Castello, Tritia Yamasaki, Wayne Poon and Kim Green of UCI worked on the study, along with Franz-Josef Muller and Jeanne Loring of the Scripps Research Institute. Funding for the study was provided by the California Institute for Regenerative Medicine and the National Institutes of Health.