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Mar 5, 2014

In Vitro Drug Discovery Platform Developed for Alzheimer's Studies

  • Researchers at Harvard say they have converted skin cells from patients with early-onset Alzheimer’s into the types of neurons that are affected by the disease. They note that this makes it possible for the first time to study this leading form of dementia in living human cells and that the door is now opened to the potential development of novel therapies more quickly.

    The study (“The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons”), led by Tracy Young-Pearse, Ph.D., and published in 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 protein (Aβ) 42, which all people produce but somehow clump together to form plaques in Alzheimer’s patients.

    “We see this mild increase in Aβ 42 in cells from patients with Alzheimer’s disease, which seems to be enough to trigger disease processes,” said Dr. 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 Aβ 38, 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, Dr. Young-Pearse and her team, including postdoctoral fellow and study first author Christina Muratore, Ph.D., 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,” explained Dr. Young-Pearse. “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.”

    “We show that treatment with Aβ-specific antibodies early in culture reverses the phenotype of increased total Tau levels, implicating altered Aβ production in fAD neurons in this phenotype,” wrote the investigators. “These studies use human neurons to reveal previously unrecognized effects of the most common fAD APP mutation and provide a model system for testing therapeutic strategies in the cell types most relevant to disease processes.”

    Clinical trials to treat neurodegenerative diseases like Alzheimer’s have a historically high failure rate, partially because potential drugs are derived from research in nonhuman models. Dr. 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.



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