Alzheimer's in a Petri Dish

Pearse, PhD, confirmed what had long been observed in mouse models—that the mutations associated with early-onset Alzheimer's disease are directly related to protein cleavage errors that cause a rise in amyloid-beta (Aβ) protein 42, which all people produce but somehow clump together to form plaques in Alzheimer's patients.

The release quotes Young-Pearse, a Harvard Stem Cell Institute Affiliated Faculty member at Brigham and Women's Hospital, as saying, "We see this mild increase in Aβ42 in cells from patients with Alzheimer's disease, which seems to be enough to trigger disease processes. We also see increases of a smaller species of amyloid-beta called Aβ38, which was unexpected as it should not be very aggregation prone. We don't fully understand what it means, but it may combine with other forms of amyloid-beta to stimulate plaque formation."

The patient-derived cells also possessed the second hallmark of Alzheimer's disease, high amounts of the tau protein, or more accurately tau that has been distorted so that the proteins tangle together. The relationship between amyloid-beta and tau is an ongoing chicken-and-egg debate in the Alzheimer's research field, with some researchers associating one or the other, or both, with the cause of the disease. But with the human cells, Young-Pearse and her team, including postdoctoral fellow and study first author Christina Muratore, PhD, could demonstrate that preventing amyloid-beta imbalances reduced levels of distorted tau.

"We used two different antibodies—one of which has been in clinical trials for Alzheimer's—to neutralize the effects of amyloid-beta and showed that you're able to rescue changes in tau," Young-Pearse said. "Not only is it important experimentally to show that tau elevation is due in some part to altered amyloid-beta accumulation, but it also shows that this is an excellent system for testing different therapeutic options."

Clinical trials to treat neurodegenerative diseases like Alzheimer's have a historically high failure rate, partially because potential drugs are derived from research in non-human models. Young-Pearse and colleagues believe that their strategy of using induced pluripotent stem cells to reprogram patient skin cells into neurons of interest could be used to predict which therapeutics will best help early-onset Alzheimer's patients.