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Alzheimer's research team employs stem cells to understand disease processes and study new treatment

Boston, MA A team of Alzheimer's disease (AD) researchers at Brigham and Women's Hospital (BWH) has been able to study the underlying causes of AD and develop assays to test newer approaches to treatment by using stem cells derived from related family members with a genetic predisposition to (AD).

"In the past, research of human cells impacted by AD has been largely limited to postmortem tissue samples from patients who have already succumbed to the disease," said Dr. Tracy L. Young-Pearse, corresponding author of the study recently published in Human Molecular Genetics and an investigator in the Center for Neurologic Diseases at BWH. "In this study, we were able to generate stem cells from skin biopsies of living family members who carry a mutation associated with early-onset AD. We guided these stem cells to become brain cells, where we could then investigate mechanisms of the disease process and test the effects of newer antibody treatments for AD."

The skin biopsies for the study were provided by a 57-year-old father with AD and his 33 year-old- daughter, who is currently asymptomatic for AD. Both harbor the "London" familial AD Amyloid Precursor Protein (APP) mutation, V7171. More than 200 different mutations are associated with familial AD. Depending on the mutation, carriers can begin exhibiting symptoms as early as their 30s and 40s. APPV7171 was the first mutation linked to familial AD and is the most common APP mutation.

The BWH researchers submitted the skin biopsies to the Harvard Stem Cell Institute, where the cells were converted into induced pluripotent stem cells (or iPSCs). Dr. Young-Pearse's lab then directed the stem cells derived from these samples into neurons specifically related to a particular region of the brain which is responsible for memory and cognitive function. The scientists studying these neurons made several important discoveries. First, they showed that the APPV7171 mutation alters APP subcellular location, amyloid-beta protein generation, and then alters Tau protein expression and phosphorylation which impacts the Tau protein's function and activity. Next, the researchers tested multiple amyloid-beta antibodies on the affected neurons. Here, they demonstrated that the secondary increase in Tau can be rescued by treatment with the amyloid -protein antibodies, providing direct evidence linking disease-relevant changes in amyloid-beta to aberrant Tau metabolism in living cells obtained directly from an AD patient.

While AD is characterized by the presence of amyloid-beta protein plaques and Tau protein tangles, observing living cell behavior and understanding the mechanisms and relationship between these abnormal protein deposits and tangles has been challenging. Experimental treatments for AD are using antibodies to try to neutralize the toxic effects of amyloid-beta, because they can bind to and clear the amyoid-beta peptide from the brain.

This study is the first of its kind to examine the effects of antibody therapy on human neurons derived directly from patients with familial AD.

"Amyloid-beta immunotherapy is a promising therapeutic option in AD, if delivered early in the disease process," said Dr. Young-Pearse. "Our study suggests that this stem cell model from actual patients may be useful in testing and comparing amyloid-beta antibodies, as well as other emerging therapeutic strategies in treating AD."

Contact: Jessica Maki
Brigham and Women's Hospital

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