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2018 Alzheimer's Association Research Grant (AARG)

APOE Isoform Specific Effects on Microglial Mediated Neuroinflammation

How do certain changes in immune cell activity affect different brain regions in Alzheimer’s?

Nicholas Fitz
University of Pittsburgh
Pittsburgh, PA - United States


Nerve cells communicate through specialized regions called “synapses” that connect one nerve cell to another. During Alzheimer’s synapses are damaged, which limits how effectively nerve cells can communicate. Poor nerve cell communication contributes to memory and cognitive decline. Certain immune cells in the brain, called microglia, can help maintain healthy nerve cell communication by removing unhealthy synapses.
Microglia perform this important function by sensing and responding to changes in their immediate vicinity, also called their microenvironment. They use proteins called “receptors” on their surfaces to sense changes in nearby cells and proteins. Microglia have many such receptor proteins on their surfaces that can sense apolipoprotein E  (ApoE). The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein. People with certain variations of the APOE gene are at an increased risk of developing Alzheimer’s. But, it is not clear exactly how these APOE variations may influence the ability of microglia to remove unhealthy synapses.

Research Plan

Dr. Nicholas Fitz and colleagues will determine how different variations of APOE change microglia function in the brain. First, the researchers will incubate microglia with different variations of the ApoE protein, in laboratory dishes and measure how well microglia can sense and respond to the unhealthy nerve cell synapses. Dr. Fitz will also identify any changes in microglia genomics (complete set of genes) and energy use (metabolism) during the experiments.
The researchers will then study how ApoE and other proteins known to be impacted in Alzheimer’s may change microenvironments in different brain regions. This will provide new information about how microglia function and impact changes in these regions. Additionally, Dr. Fitz will collect microglia from mice that have been genetically-engineered with high and low risk variations of APOE, focusing on three different brain regions known to play important roles in Alzheimer’s.
Dr. Fitz plans to validate their findings by measuring microglia function in brain tissue samples donated by people who had Alzheimer’s.


This study will provide new insights into how immune cells in the brain detect and respond to one of the earliest effects of Alzheimer’s - damage of synapses. The results could also clarify how different variations of APOE change brain microenvironments and influence how immune cells in these regions can function. This could help researchers understand why people with certain genetic risk factors for Alzheimer’s experience different brain changes during Alzheimer’s progression.

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