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2012 Grants - Sakurai
Functional Analysis of Neurons Derived From Alzheimer's Patient iPSCs
Mikako Sakurai, Ph.D
New York, New York
2012 New Investigator Research Grant
Alzheimer's disease research has traditionally involved the use of rodents genetically engineered to develop symptoms of the disease. Yet rodent models can never perfectly replicate the pathologies of human Alzheimer's. In recent years, some investigators have tried to overcome this limitation by engineering human brain cells in the laboratory. This process involves taking human fibroblasts (connective tissue cells) and genetically reprogramming them into "induced pluripotent stem cells" (iPSCs). Such stem cells can, in turn, be induced to develop into neurons. The use of iPSC-derived neurons has the potential to reveal more precise information about how Alzheimer's disease develops and progresses in humans.
Mikako Sakurai, Ph.D., and colleagues have had considerable success in developing neurons with the iPSC process. For their current project, they propose to develop and study neurons derived from the fibroblasts of healthy people and people with inherited, early-onset Alzheimer's. Each set of neurons will be collected in a cell culture system. The researchers will then determine whether their two cultures show differences in the activity of their synapses. Synapses are the tiny channels through which brain cells send and receive chemical messages. In Alzheimer's disease, these channels become dysfunctional and promote cognitive decline. The investigators hypothesize that their Alzheimer's cells being cultured may reveal evidence of synaptic excitotoxicity—a process in which the overstimulation of synapses leads to synaptic dysfunction. Dr. Sakurai's team will also examine whether cultured cell cultures show differing levels of beta-amyloid and tau—two compounds that tend to accumulate in the Alzheimer's brain—as well as differing levels of abnormal cell death.
Results of this study could clarify the role that excitotoxicity plays in dementia-related synaptic decline. Dr. Sakurai's work should also confirm the value of iPSC-induced neurons in Alzheimer's research.