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2018 Alzheimer's Association Clinician Scientist Fellowship (AACSF)

Tau aggregation and toxicity in patient derived iPS-neurons

Could a new type of cell grown in a laboratory dish reveal how tau protein harms nerve cells during Alzheimer’s?

Derek Oakley
Massachusetts General Hospital
Boston, MA - United States


Tau protein, which normally helps transport nutrients and maintains nerve cell structure, becomes abnormally modified during Alzheimer’s. The modifications cause the tau proteins to aggregate into toxic tangles that can spread between nerve cells. Tau tangles are one of the hallmarks of Alzheimer’s as well as other brain diseases and are believed to contribute to memory loss and cognitive decline. However, it is not entirely clear how tau tangles are associated with nerve cell dysfunction, or if they are a direct cause of nerve cell death.

Research Plan

Dr. Derek Oakley and colleagues will develop and test a new system to study how tau tangles affect nerve cells. In laboratory dishes, the researchers will grow special type of stem cells called induced pluripotent stem cells (iPS) donated by cognitively unimpaired people and also by those who had Alzheimer’s. Dr. Oakley will allow these stem cells to develop into nerve cells, and then expose them to brain tissue samples containing tau. Since some of the samples were donated by people who had Alzheimer’s, they contain the many different forms of tau associated with the Alzheimer’s.
Dr. Oakley’s team will use time-lapse imaging to monitor how tau from the brain samples begins to aggregate inside the nerve cells in the laboratory dish. Dr. Oakley believes that nerve cells derived from people who had Alzheimer’s will be more likely to aggregate tau than cells from cognitively unimpaired people. The researchers will also sort tau proteins in the brain samples to identify which forms contribute to most toxic tau aggregation in the nerve cells.


The study results could reveal which of the many forms of tau found in tangles are most harmful to nerve cells. It may also clarify mechanisms of tau-mediated toxicity of the nerve cells. Finally, the study will produce a scalable model of cells in a laboratory dish that could be used by other Alzheimer’s researchers for their experiments and drug discovery applications.

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