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.

"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."

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. 

"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.