Of mice and men: UCI scientists show that neural stem cells can rescue memory in mice with advanced Alzheimer's disease

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.

IRVINE, Calif.—Scientists at the University of Californiain Irvine (UCI) say neural stem cells helped rescue memory in mice withAlzheimer's disease. The team successfully used injections of neural stem cellsto repair damaged brain cells.

Frank LaFerla, director of UCI's Institute for MemoryImpairments & Neurological Disorders, or UCI MIND, and co-author of thestudy that appeared recently in the Proceedings of the National Academy ofSciences, said that mice geneticallyengineered to have Alzheimer's performed markedly better on memory tests amonth after mouse neural stem cells were injected into their brains. The stemcells secreted a protein that created more neural connections, improvingcognitive function.

"Essentially, the cells were producing fertilizer for thebrain," LaFerla says.
 
The findings also raise hopes for a potential treatment forthe leading cause of elderly dementia that afflicts 5.3 million people in theUnited States.

"It gives new impetus to evaluate cell-based therapies as apotential treatment for Alzheimer's disease," Laferla says. "It is important topoint out, that it may not necessarily be a cell that proves to be therapeuticbut a factor identified from these studies. Certainly, our original studypoints to brain-derived neurotrophic factor (BDNF) as playing a benefical role, hence BDNF mimetics maybe useful for treating Alzheimers disease."

Lead author Mathew Blurton-Jones, LaFerla and colleaguesworked with older mice predisposed to develop brains lesions called plaques andtangles that are the hallmarks of Alzheimer's.
 
To learn how the stem cells worked, the scientists examinedthe mouse brains. To their surprise, they discovered that just 6 percent of thestem cells had turned into neurons. The majority became the other two maintypes of brain cells, astrocytes and oligodendrocytes. The stem cells didn'timprove cognition by becoming new neurons, nor did they act by reducing thenumber of plaques and tangles.

Rather, the stem cells were found to have secreted a proteincalled BDNF. This caused existing tissue to sprout new neurites, strengtheningand increasing the number of connections between neurons. When the teamselectively reduced BDNF from the stem cells, the benefit was lost, providingstrong evidence that BDNF is critical to the effect of stem cells on memory andneuronal function.

"If you look at Alzheimer's, it's not the plaques andtangles that correlate best with dementia; it's the loss ofsynapses—connections between neurons," Blurton-Jones says. "The neural stemcells were helping the brain form new synapses and nursing the injured neuronsback to health."

Diseased mice injected directly with BDNF also improvedcognitively but not as much as with the neural stem cells, which provided amore long-term and consistent supply of the protein.

LaFerla says the result gives scientists "a lot of hope thatstem cells or a product from them, such as BDNF, will be a useful treatment forAlzheimer's."

LeFerla notes that the team was skeptical that stem cellswould be effective simply because the Alzheimer brain contains damage to manyregions. 

"Initially, we thought that stem cells would lead to repairthrough a replacement model," he says. "Instead, we found that the stem cellswere performing a nursing function, producing a neurotrophic factor, BDNF,which our studies pointed to as causing the improvement in memory. The factthat the stem cells were performing a nursing function in the AD brain suggeststhat one doesn't have to target them to multiple brain regions in order to seeefficacy."
 
Although the experiment was only done on mice, the researchersare confident that the technique may one day be used on humans to restorememory lost during the late stages of Alzheimer's.
 
Whether the experiment can be replicated and the findingstranslated to human populations remains to be seen.

"We haven't yet evaluated the long term effects of the stemcell treatments in mice, but we are hopefully that it will allow for somereversal of cognitive function, not just stabilization," notes LeFerla. "Theseexperiments 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 ofrestoring function in the mouse. 

"There are many human cell lines that are available andclinical application requires that we identify the appropriate line to developand prepare under good manufacturing procedures," he notes. "There are manyquestions that remain to be addressed, such as whether the sex of the cellmakes a difference, i.e., will implantinga male cell into a female brain matter, or whether the genotype of the cell isimportant—for example, ApoE4 is a risk factor for Alzheimer's disease, but ifthe 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 thedevelopment 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 KimGreen of UCI worked on the study, along with Franz-Josef Muller and JeanneLoring of the Scripps Research Institute. Funding for the study was provided bythe California Institute for Regenerative Medicine and the National Institutesof Health.



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