Cell Therapy in Mice Protects Against Alzheimer’s Changes

BrightFocus Research Moves Field Forward

This research was supported by BrightFocus

University of California, Irvine (UCI) researchers, including BrightFocus-funded researcher Frank M. LaFerla, PhD, and his colleague, lead investigator Mathew Blurton-Jones, PhD, have published positive findings from mice studies that suggest cell therapy slows down brain changes and symptoms linked to Alzheimer’s disease.

Results from their preclinical study in mice were published in Stem Cell Research & Therapy  on April 16 (Blurton-Jones M, et al, 2014).

Potential Advantages of Cell Therapy

Increasingly, attention is being given to the role of transplanted cells in helping the brain defend itself against the amyloid beta plaques and tau-ridden neurofibrillary tangles associated with Alzheimer’s disease. Left untreated, this debris field, in most cases, becomes toxic to neurons, and is associated with memory loss, cognitive difficulties, and other outward symptoms of Alzheimer’s disease.

Considerable research is aimed at finding drugs and biologic agents to stop this process, but they share a common challenge: the brain is protected by a blood-brain-barrier that protects it from foreign substances. While generally helpful, this barrier makes it challenging to deliver drugs and other substances to the parts of the brain where they might do the most good.

To overcome this drawback, researchers have hypothesized that cells engineered to start or stop the expression of enzymes and other neurochemicals might be an effective therapy. Once transplanted, those cells then set in motion effects that are replicated throughout the brain tissue, and thus might prove capable of regulating the multiple pathways and regions affected by Alzheimer’s disease for longer periods of time than with locally delivered therapies.

Most scientists believe that ultimately, early intervention to stop Alzheimer’s will require combination approaches.

BrightFocus Research Set Stage for Present Findings

Dr. LaFerla et al, in earlier studies, had demonstrated that transplanting neural stem cells in mice (called murine NSC transplantation) markedly improves cognitive function, synaptic connectivity and neuronal survival in mice models of Alzheimer’s disease. In their BrightFocus-funded research, they looked more closely at one of the neuroprotective proteins linked with improved cognition in mice—called brain-derived neurotrophic factor—and investigated whether it could be administered alone or worked better when delivered through murine NSC transplantation.

This most recent study was led by Mathew Blurton-Jones, PhD, assistant professor of neurobiology and behavior at UCI. He and fellow researchers, including Dr. LaFerla, zeroed in on the enzyme neprilysin, which breaks down amyloid beta protein. They conducted mice experiments to see if NSC transplantation worked as a mechanism to upregulate neprilysin production.

"Studies suggest that neprilysin decreases with age and may therefore influence the risk of Alzheimer's disease," Blurton-Jones explained. "If amyloid accumulation is the driving cause of Alzheimer's disease, then therapies that either decrease amyloid beta production or increase its degradation could be beneficial, especially if they are started early enough."

To test their hypothesis, the team injected the brains of two different mouse models with genetically modified murine NSCs that produced 25-times more neprilysin than control NSCs, but were otherwise equivalent. Genetically modified and unmodified control NSCs were then transplanted into areas of the brain most affected by Alzheimer's disease. The mice transplanted with genetically modified NSC were found to have a significant reduction in amyloid beta plaques compared to the controls. The effect remained for a month after NSC transplantation.

More Power to the Mouse Model

Someday these results might be applied to a human treatment approach. Conceivably, neprilysin-expressing cells might promote the growth of brain connections in symptomatic patients and also target and reduce amyloid beta pathology. However, the work is “preclinical”—still in mice models—and much more work needs to be done before such an approach could be tested in humans.

Experimentation will continue using the two mouse models the team has developed—in themselves a research breakthrough. Most previous studies of cell therapy for Alzheimer’s disease have been done using a single mouse model, and variability has weakened the results.

Dr. LaFerla is credited with developing the very first mouse model engineered to accumulate the beta amyloid plaques and tau tangles of Alzheimer’s disease.

“Everyone uses the mouse,” said one of his colleagues in a 2006 article profiling LaFerla’s work. “His mouse is among the most important tools available to Alzheimer’s researchers.”