Modified stem cells may offer way to treat Alzheimer's disease

A new study suggests genetically modified stem cells may offer a new way to treat Alzheimer's disease. When implanted in mice bred to have symptoms and brain hallmarks of Alzheimer's, they increased connections between brain cells and reduced the amyloid-beta protein that accumulates to form plaques that clog up the brain.

A report on the study, led by neurobiologists at the University of California (UC) - Irvine, is published in the journal Stem Cell Research & Therapy.

While the team showed that the approach worked in two different mouse models of Alzheimer's, they say there is still a long way to go before we know if it will benefit patients with the human form of the disease.

Alzheimer's is a progressive disease where brain cells stop working and lose connections with each other, and eventually die off. This gradual wasting of the brain is what leads to memory failure, personality changes, difficulty coping with day-to-day living and other symptoms.

There are two distinct hallmarks of Alzheimer's disease: deposits of tau protein that accumulate inside brain cells, and plaques of amyloid protein that clog up the spaces between brain cells. It is not easy to investigate how these changes take place in living human brains, which is why mice bred to have similar hallmarks are so useful in research.

Hope of targeting brain-clogging proteins that build up in Alzheimer's

For some time now, researchers have been looking into ways of treating Alzheimer's that target the build-up of the tau and amyloid proteins, either with drugs or non-drug approaches such as stem cells.

Stem cells are cells that have the potential to become virtually any type of cell in the body. By altering the genes of stem cells, the idea is to make them behave in a slightly different way when they transform into the cell of interest.

In this study, the researchers were interested in making brain cells that increase levels of an enzyme neprilysin, which is known to break down amyloid-beta and shows lower activity in the brains of people with Alzheimer's disease.

The study's first and corresponding author, Mathew Blurton-Jones, an assistant professor of neurobiology and behavior at UC-Irvine, explains that there is evidence that neprilysin decreases with age and may, therefore, affect the risk of developing Alzheimer's disease. This made the team wonder, he says:

"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."

Genetically altered brain stem cells reduced amyloid-beta plaques

They tested their idea on two strains of mice bred to have symptoms and brain hallmarks of Alzheimer's. The two mouse models are called 3xTg-AD and Thy1-APP. Most studies only use one mouse model, but a criticism that is often leveled at them is there can be variations between models.

They injected the mice with brain stem cells that were genetically modified to over-express the gene that codes for neprilysin. They also injected other mice with unaltered stem cells; these were the controls.

They found the genetically altered brain stem cells produced 25 times more neprilysin than the control stem cells but were otherwise equivalent to them.

The genetically altered stem cells produced 25 times more neprilysin and a significant reduction in amyloid-beta plaques, compared with the controls.

Then, the team transplanted the genetically modified and control stem cells into the hippocampus or subiculum of the mice brains. These two brain areas are the ones most affected by Alzheimer's disease.

The brains of mice that received the genetically modified brain stem cells showed a significant reduction in amyloid-beta plaques compared with the controls. This reduction persisted for at least a month after transplantation.

The researchers note that using modified stem cells offers a potential advantage to unmodified stem cells because unmodified stem cells would only promote growth of brain connections, whereas, as this study shows, genetically modified ones could also target and reduce amyloid plaques.

The team notes there is a long way to go yet before this approach can be tested in humans. Among the questions that need answering are: will it work with soluble forms of amyloid-beta? Does it improve cognition more than transplanting unmodified brain stem cells?

Prof. Blurton-Jones says that by studying two different mouse models they can increase confidence that their findings are meaningful and broadly applicable to Alzheimer's, but, "there is clearly a great deal more research needed to determine whether this kind of approach could eventually be translated to the clinic."

Funds from the California Institute for Regenerative Medicine, the Alzheimer's Association, the American Health Assistance Foundation and the Else-Kröner Fresenius Stiftung helped finance the study.

Meanwhile, clinical experts recently reported how a new drug could reverse age-related memory impairment. Researchers found rats with age-related cognitive decline showed improved memory function when they gave them a drug that reduced high levels of a brain chemical called GABA, which can disrupt working memory when there is too much of it.