Tracy L. Young-Pearse, PhD

BWH researchers have been able to study the underlying causes of Alzheimer’s disease (AD) and develop assays to test newer treatment approaches that use stem cells derived from related family members with a genetic predisposition to Alzheimer’s. Moreover, 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.

“In the past, research of human cells impacted by Alzheimer’s disease has been largely limited to postmortem tissue samples from patients who have already succumbed to the disease,” said Tracy L. Young-Pearse, PhD, corresponding study author, BWH Center for Neurologic Diseases. “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 Alzheimer’s. 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 the disease.”

Looking specifically at the “London” familial Alzheimer’s disease Amyloid Precursor Protein (APP) mutation V7171—the first mutation ever linked to familial AD—researchers showed that the 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-beta-protein antibodies, providing direct evidence linking disease-relevant changes in amyloid-beta to aberrant Tau metabolism in living cells obtained directly from a patient with AD.

The study was published Feb. 26, 2014 in Human Molecular Genetics.