2023 Alzheimer's Association Research Grant (AARG)
Excitability Imbalance in Preclinical Alzheimer's Disease
What are the mechanisms by which nerve cells in the brain become overly active in Alzheimer’s?
Nien-Pei Tsai, Ph.D.
The Board of Trustees of the University of Illinois Urbana-Champaign
Urbana, IL - United States
Background
Recent studies suggest that nerve cells in the brain can become overly excited in Alzheimer's. This process, called hyperexcitability, can overstimulate nerve cells and synapses (specialized structures that nerve cells use to send signals to one another to communicate). Hyperexcitability can also lead to cognitive decline, seizures, and nerve cell death in early Alzheimer’s. However, the mechanisms by which nerve cells become overly active in the early stages of Alzheimer’s are unknown.
In initial research, Dr. Nien-Pei Tsai and colleagues identified a specific protein, called postsynaptic density protein-95 (PSD-95), that plays a role in nerve cell hyperexcitability. The team also found that high levels of PSD-95 are associated with beta-amyloid plaques, one of the hallmark brain changes in Alzheimer’s.
Research Plan
Building on the initial findings, Dr. Tsai and the team will examine the mechanisms by which PSD-95 contributes to beta-amyloid plaque formation and cognitive decline in Alzheimer’s. They will do this using genetically engineered Alzheimer’s-like mice that accumulate amyloid plaques in the brain. First, they will measure nerve cell excitability in the brains of these mice with or without the presence of PSD-95. They will also examine synapse damage and seizures in the same mice. Lastly, the team will examine whether reducing PSD-95 levels in the brains of genetically engineered Alzheimer’s-like can prevent cognitive decline.
Impact
Results from this project could improve our understanding of nerve cell activity in cognitive decline and Alzheimer’s. They could also identify new targets that prevent nerve cell hyperactivity and slow Alzheimer’s progression.