Stem cells shed light on potential anti-Alzheimer’s compound

Amyloid plaques in Alzheimer's disease
Amyloid plaques are believed to be the culprit behind the memory-stealing effects of Alzheimer's.

Toxic deposits of the proteins amyloid beta and tau in the brain have been implicated in Alzheimer’s disease, but the understanding of exactly how these proteins interact to cause dementia is still largely a mystery. Scientists at the University of Washington are using stem cells from Alzheimer’s patients to study the two proteins—and they’ve hit upon a compound that seems to lessen the buildup of them in brain cells.

The team started by taking skin cells from both Alzheimer’s patients and healthy people and transforming them into pluripotent stem cells, which have the ability to become any cell in the body. They then used those stem cells to create neurons with the same genetic makeup as that of the patients who donated their skin samples. The neurons created from the skin of Alzheimer’s patients retained the tendency to create excess amyloid beta and tau—allowing the researchers to use the cells as mini laboratories.

They were particularly interested in finding ways to manipulate “endosomes,” which are vehicles that move proteins around in cells. Past research suggested that amyloid-beta and tau clump up in cells because of defects in endosomes. The scientists focused on a protein network called the retromer, which helps endosomes function properly in cells.

Sponsored By Syneos Health

Blazing a Trail to Clinical Trial Diversity: Four-Part Webinar Series from Syneos Health, Featuring Pharma, Clinical Research and Community Health Leaders

This series will identify obstacles that stifle appropriate patient diversity in trials; unpack the organizational overhaul needed; share how sponsors, patients & investigators have come together to overcome hurdles; and explore how policy innovations can move the industry forward.

The researchers administered a compound called R33 to their lab-grown stem cells and then measured production of amyloid beta and tau. R33 had been shown in animal studies to boost the function of the retromer. And, in fact, it did lead to a “considerable reduction” in the production of both amyloid-beta and tau, according to a press release. The study was published in the journal Stem Cell Reports.

RELATED: A personalized MS treatment built from skin stem cells

Drugs that target amyloid plaques have been disappointing in Alzheimer’s. Witness the failures of Eli Lilly’s solanezumab and Merck’s verubecestat. But scientists who study Alzheimer’s have not given up on the notion that preventing the protein from building up in the brain could be an effective way of preventing the descent into memory loss.

In February, researchers at the Cleveland Clinic showed they could reverse the development of amyloid plaques in the brains of mice by slowly depleting levels of BACE1, which is known to play a role in the production of the toxic protein. But because BACE1 is involved in several normal processes in the body, figuring out how to translate the findings into a therapy will be challenging.

The University of Washington researchers hope to use their lab-grown stem cells to further scrutinize the role of both amyloid beta and tau in Alzheimer’s. One popular hypothesis is that the production of amyloid beta drives the buildup of tau. But the experiments with R33 suggested that tau works independently of amyloid beta—providing evidence of a still-undiscovered upstream force that causes both harmful proteins to form brain plaques.

“So one thing we're going to work on going forward will be using these cell lines to identify what this upstream defect might be,” said Jessica Young, assistant professor of pathology at the UW School of Medicine, “and whether it, too, could be a target for new therapeutics to treat Alzheimer's."