Blood Stem Cell Therapy for Alzheimer’s Disease Shows Promise in Mice

The Context: Microglia are the immune cells of the brain and play an important role in preventing degeneration of neurons. Scientists have identified genetic variations in microglia (specifically, in a gene called TREM2) that lead to microglia dysfunction and are associated with an increased risk of developing Alzheimer’s disease.

The Study: By transplanting healthy blood stem and progenitor cells into mice with a defective TREM2 gene, the transplanted cells were incorporated into the body and replaced dysfunctional microglia. The study, led by NYSCF – Robertson Stem Cell Investigator Alumnus Marius Wernig, MD, PhD, of Stanford Medicine and first authored by NYSCF – Druckenmiller Fellow Yongin Yoo, PhD, appears in Cell Stem Cell.

The Importance: This study is an important proof-of-concept showing that a cell therapy for Alzheimer’s could have efficacy in patients with non-familial forms of the disease.

“This cell therapy approach is unique in the field because most researchers are working to find pills or injectables to treat Alzheimer’s disease,” Dr. Wernig told Stanford Medicine News.

Cell therapies are exciting because they can address the root of a disease by replacing diseased cells with healthy ones. And in this case, the therapy could help millions of people with non-inherited forms of Alzheimer’s, for which mutations in TREM2 are rampant.

“Certain genetic variants of TREM2 are among the strongest genetic risk factors for Alzheimer’s disease,” explained Dr. Wernig. “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.”

Brand New Brain Cells

The team’s therapy was first tested by introducing healthy blood stem and progenitor cells into mice with a defective TREM2 gene.

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

But do the new microglia help heal the brain? 

“Indeed, in the transplanted mice we saw a clear reduction in the deposits of amyloid plaques [a hallmark of Alzheimer’s disease] normally seen in TREM2-deficient mice,” said Dr. Wernig.

The scientists reported that the new microglia were able to carry out their typical cleanup duties, but aren’t exactly the same as a native brain cell.

“These differences might in some way have their own detrimental effect,” Dr. Wernig said. “We have to look at that very carefully.”

The team will continue developing and testing their therapy, and are considering engineering the transplanted cells to have ‘supercharged’ TREM2 activity, which could accelerate healing. 

It is important to note that the current procedure would be risky in humans because blood stem cell transplantation requires that patients undergo a toxic chemotherapy to destroy native blood stem cells. However, many scientists are working toward safer transplantation methods, which this therapy could employ.

Journal Article:

A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease
Yongjin Yoo, Gernot Neumayer, Yohei Shibuya, Marius Marc-Daniel Mader, Marius Wernig. Cell Stem Cell. 2023. DOI: 10.1016/j.stem.2023.07.006