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2023 Alzheimer's Association Research Fellowship (AARF)

Uncovering Mechanisms of Neuronal Hyperexcitability in Tauopathies

How do nerve cells become overly active in brains with high levels of disease-related tau protein?

Steven Boggess, Ph.D.
University of California, San Francisco
San Francisco, CA - United States


A growing number of studies suggest that brain cells can become overly excited in Alzheimer's. This toxic process, known as excitotoxicity, can overstimulate nerve cells and synapses (specialized structures that nerve cells use to send signals to one another to communicate).  Excitotoxicity can also lead to cognitive decline and nerve cell death. According to current research, areas of the brain that experience excitotoxicity also have build-up of abnormal tau. This protein is known to form tangles that are a hallmark of Alzheimer’s and other tau-related diseases (or tauopathies). Although tau appears to play a role in excitotoxicity, scientists do not yet understand the nature of this role or its underlying mechanisms. 

In initial research, Dr. Steven Boggess and colleagues measured excitotoxicity in nerve cells derived from iPSCs (induced Pluripotent Stem Cells). iPSCs are specialized stem cells engineered from adult human tissue and then reprogrammed into any type of cell in the human body, including nerve cells. The research team found that iPSC neurons with a disease-related tau variation (called V337M) had higher activity levels than cells without this variation. The team then identified a gene called NSD1 that appears to regulate tau to either promote or prevent excitotoxicity.  

Research Plan

Dr. Boggess and colleagues will now conduct a larger study to assess how NSD1 impacts the distribution and levels of tau in iPSC neurons with and without the V337M tau variation. They will then examine whether NSD1’s ability to regulate tau becomes impaired in tauopathies and leads to nerve cell excitotoxicity. As part of this experiment, the team will genetically analyze the nerve cells to find other genes that may work with NSD1 to promote abnormal tau build-up and nerve cell dysfunction. Next, they will look for other genetic mechanisms underlying the association of tau and excitotoxicity – including mechanisms that impact synapses.     


Results from this project could improve our understanding of tau’s role in cognitive decline and brain disease. They could also identify new genetic targets that prevent disease-related alterations in nerve cell activity and slow disease progression. 

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