Scientists at Stanford University School of Medicine are testing a new approach to treating Alzheimer's disease in mice. The therapy involves transplanting blood stem cells from healthy mice into diseased mice to help replace defective nerve cells.
Some forms of Alzheimer's disease are linked to certain genetic variations in a type of brain cell called microglia. Microglia are the brain’s resident immune cells that constantly monitor this vital organ, looking for signs of pathogens, damage, or metabolic waste buildup and initiating repairs. The Stanford team focused on a particular gene called TREM2.
"Certain genetic variants in TREM2 are among the strongest genetic risk factors for Alzheimer's disease. The data convincingly suggest that microglial dysfunction can contribute to neurodegeneration in the brain, so it makes sense that restoring defective microglial function might be a way to combat neurodegeneration in Alzheimer's disease."
To conduct the study, Wenig experimented with mice that had a defect in the TREM2 gene and transplanted them with blood stem and progenitor cells from healthy mice. It was found that the transplanted cells were able to rebuild the recipient's blood system and even form new cells in the brain that looked and functioned like microglia.
Importantly, these new microglia-like cells replaced many of the recipients' original microglia and appeared to restore their function. It also reduced other markers of Alzheimer's disease, including the buildup of amyloid plaques.
"Our study showed that most of the original microglia in the brain were replaced by healthy cells, restoring normal TREM2 activity," Wenig said. "In fact, in the transplanted mice, we saw a significant reduction in the amyloid plaque deposition typically seen [in] TREM2-deficient mice."
The researchers also said that the effect could be enhanced by first engineering the transplanted cells to have stronger TREM2 activity. However, while this proof-of-concept study looks promising, there are some major caveats. First, the grown replacement cells resemble microglia, but are not identical to native microglia—a difference that could lead to other complications.
"These differences may have adverse effects in some way. We have to look at this carefully," Wenig said.
The bigger problem is that this treatment is invasive and risky for humans. Before transplanting new hematopoietic stem cells, the patient's own native hematopoietic stem cells need to be destroyed first, using radiation or chemotherapy. People with leukemia sometimes receive these treatments, but the procedures can be dangerous and unpleasant. Less toxic approaches are currently being investigated, and if any of these come to fruition, the team says they could eventually find their way into Alzheimer's treatments.
The research was published in the journal CellStemCell.