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2021 AD Strategic Fund: Neuroimmune (ADSF)

Apolipoprotein Mutations and Astrocyte Function in Alzheimer's Disease

How do certain gene variations impact support cells found in the brain in Alzheimer’s?

Shane Liddelow, Ph.D.
New York University School of Medicine
New York, NY - United States


Astrocytes, commonly known as “support cells,” are the most numerous cell type in the brain. They play an important role in supporting nerve cell function in the brain. Astrocytes also make several kinds of proteins, including clusterin. The clusterin protein supports many biological processes throughout the body, such as  transportation of fats and modulation of the immune system. However, the exact role of clusterin in the brain is not entirely clear.

Several studies have connected variations in the gene CLU that provides instructions for making clusterin with increased risk of Alzheimer’s and other dementia. Researchers have also found clusterin attached to beta-amyloid plaques – one of the hallmark brain changes observed in the brains of people with Alzheimer’s. Studies show that older adults and individuals with late-onset Alzheimer’s may have especially high levels of clusterin circulating in their bodies. Studies indicate that clusterin may directly interact with the protein ApoE. The gene apolipoprotein E (APOE) provides instructions for making the ApoE protein that is believed to help carry fats throughout the body. 

Dr. Liddelow and colleagues will study how variations in the gene CLU that provides instructions for making clusterin may impact the health and functionality of astrocytes. The researchers will determine if these variations may change the way the clusterin protein interacts with specific variations of ApoE including ApoE-e2, ApoE-e3, and ApoE-e4. The variation ApoE-e4 is thought in some populations to impact a person’s risk of developing Alzheimer’s.

Research Plan

Dr. Liddelow’s team will develop several model systems for the study. First, the researchers will introduce different variations of the human CLU gene into astrocytes taken from mice. They will then assess the health of astrocytes using sophisticated microscopic techniques and through a series of biochemical tests. Dr. Liddelow’s team will also mix the astrocytes with other types of brain cells and observe how the cells interact with each other. Together, these experiments could help Dr. Liddelow understand the impact of each CLU variation on general astrocyte function. 

Finally, the researchers will introduce the human APOE gene variations into astrocytes taken from mice. Using this model, the research team will study how the interplay between CLU and APOE may impact the health and function of astrocytes.


The study results could determine how interactions between certain genes may impact the function of the most numerous support cell in the brain, in disease state. If successful, the study model could provide a platform to further study genes associated with Alzheimer’s and understand the larger role played by astrocytes in impacting brain function.

Made possible through the generous funding from an Anonymous Foundation and the Alzheimer’s Association.

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