Alzheimer's in a dish

Harvard stem cell scientists have successfully converted skins cells from patients with early-onset Alzheimer's into the types of neurons that are affected by the disease, making it possible for the first time to study this leading form of dementia in living human cells. This may also make it possible to develop therapies far more quickly and accurately than before.

The research, led by Tracy Young-Pearse, PhD, and published in the journal Human Molecular Genetics, 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.

"We see this mild increase in Aβ42 in cells from patients with Alzheimer's disease, which seems to be enough to trigger disease processes," said Young-Pearse, a Harvard Stem Cell Institute Affiliated Faculty member at Brigham and Women's Hospital. "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.

Alzheimer's disease comes in two forms. Both possess the well-known cognitive decline and memory loss, but occur at different times in the patient's life. Early-onset or familial Alzheimer's, which can begin to manifest in a person's 30s, 40s, and 50s, is the less common form. In these cases, genetic mutations have been inherited that lead to the disease. The more common sporadic or late-onset Alzheimer's occurs in a person's 70s, 80s, and 90s, and while certain genes may affect disease prognosis it is not associated with specific mutations.