Researchers find success using stem cell therapy in mouse model of Alzheimer’s disease

Aug. 22, 2023

Researchers at the institute have shown that cell transplantation can be used to treat Alzheimer’s disease in a mouse model, raising the hope that cell therapy might be a viable treatment for human Alzheimer’s patients in the future. 

“This is a great proof-of-concept demonstration that we can replace defective brain cells with transplanted blood cells,” says Professor of Pathology Marius Wernig, MD, PhD. “This cell therapy approach is unique in the field because most researchers are working to find pills or injectables to treat Alzheimer’s disease.”

Despite extensive research on Alzheimer’s disease, the cause and development of the neurodegenerative disorder is not well understood. Most therapies focus on clearing the buildup of amyloid plaques found in familial Alzheimer’s disease (AD), even though there is not a clear connection between clinical signs of AD and the presence of these plaques. 

There is, however, a clear association between non-familial, late onset AD and various mutations in microglia—brain cells that protect other brain cells against invaders and function as a cleanup crew, taking out the metabolic trash that can accumulate in the working brain 

Scientists looking at Alzheimer’s disease in humans have observed that certain genetic variations in brain cells called microglia show a strong correlation with their risk of getting AD. One of the strongest associations is between AD and a microglia associated gene calledTREM2. “In fact, genetic variants of TREM2 are among the strongest genetic risk factors for Alzheimer’s disease,” Wernig says.

“The data are convincing that microglial dysfunction can cause neurodegeneration in the brain, so it makes sense that restoring defective microglial function might be a way to fight neurodegeneration in Alzheimer’s disease,” Wernig said. 

Wernig and his colleagues worked with a mouse model of Alzheimer’s disease in which the mice were bred to have a defective TREM2 gene. They then transplanted blood stem and progenitor cells from mice that had normal TREM2 function into the mice with a defective TREM2 gene. By using a fluorescent tag that would mark only cells that developed from the transplanted, normal cells, the researchers were able to show that some of the transplanted cells were able to migrate into mouse brain and become cells that looked and behaved like microglia. 

“We showed that most of the brain's original microglia were replaced by healthy cells which led to a restoration of normal TREM2 activity,” Wernig said. 

Next, they asked if the restored TREM2 activity was enough to positively affect the pathologies that the TREM2 deficient mice exhibited. “Indeed, in the transplanted mice we saw a clear reduction in the deposits of amyloid plaques that normally afflict TREM2-deficient mice,” Wernig said. They were also able to show improvement in a number of other disease-associated signatures that indicate that restoring the function of this one gene has widespread positive effects. 

Wernig and colleagues point out that they could potentially even transplant cells that had been engineered to have supercharged TREM2 activity for even greater effect. They caution, however, that the microglia derived from the transplanted cells are slightly different than the natural microglia in the brain. “These differences might in some way have their own detrimental effect on neurodegeneration,” Wernig said. “We have to look at that.” 

The other caution is that transplantation of the blood stem cells require a highly toxic preconditioning to kill off native blood stem cells. This would make the current procedure highly risky if it were eventually developed into a human therapy. However, many researchers, including some at the Institute for Stem Cell Biology and Regenerative Medicine, are developing less toxic methods of preconditioning for stem cell transplants.