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2023 Alzheimer's Association Research Fellowship (AARF)

Uncovering Mechanisms of Axonal Pathology in Alzheimer's disease

How do sphere-like structures around amyloid plaques hinder brain cell communication in Alzheimer’s?

Yifei Cai, Ph.D.
Yale University
New Haven, CT - United States


A hallmark of Alzheimer’s is the clumping of beta-amyloid, a protein fragment, into sticky plaques within the brain. . According to recent studies, spherical structures that develop around plaques may promote dementia-related cognitive decline. These structures, known as plaque-associated axonal spheroids (PAAS), develop from axons, the long, thread-like extensions that nerve cells use to communicate with each other. Studies have shown that PAAS structures may hinder brain cell communication, especially when they become numerous or large in size. Scientists, however, do not know exactly how the structures form or how they promote axonal dysfunction and cognitive loss.

Research Plan

Dr. Yifei Cai and colleagues will investigate biological mechanisms underlying the role of PAAS in Alzheimer’s. The researchers will use a specialized type of stem cell collected from adult human tissue called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the human body and grown in laboratory dishes. The team will reprogram the iPSCs into nerve cells, astrocytes (the brain’s “helper cells”) and microglia (the brain’s chief immune cells).  

The researchers will expose the iPSC-derived brain cells to beta-amyloid, and, as amyloid plaques form, they will examine how PAAS develop around the plaques. Specifically, they will assess the size and quantity of PAAS structures, as well as the role played by astrocytes and microglia in their development. They will also measure levels of dementia-related tau, another hallmark Alzheimer’s protein, in the PAAS. Finally, the team will modify their iPSC-derived brain cells to determine whether altering certain protein levels in the cells may reduce PAAS formation and growth and promote nerve cell communication.        


Results from this project could shed new light on how brain cell activity becomes altered in Alzheimer’s and leads to memory loss and other forms of cognitive decline. They could also promote novel therapies that slow cognitive decline by targeting PAAS formation. 

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